Triazine compounds as pi3 kinase and mtor inhibitors

ABSTRACT

Compounds of formula I 
     
       
         
         
             
             
         
       
         
         
           
             wherein: 
             R 1  is 
           
         
       
    
     
       
         
         
             
             
         
       
     
     and R 2 , R 4 , and R 6-9  are defined herein, and pharmaceutically acceptable salts and esters thereof. These compounds inhibit PI3 kinase and mTOR, and may be used to treat diseases mediated by PI3 kinase and mTOR, such as a variety of cancers. Methods for making and using the compounds of this invention are disclosed. Various compositions containing the compounds of this invention are also disclosed.

FIELD OF THE INVENTION

This invention relates to 2,4,6-substituted [1,3,5]triazine compounds inwhich one substituent is an optionally substituted morpholino,tetrahydropyranyl or dihydropyranyl group, which inhibit PI3 kinase andmTOR, to processes for preparing them, to methods of treatment usingthem and to pharmaceutical compositions containing them.

BACKGROUND OF THE INVENTION

Phosphatidylinositol (hereinafter abbreviated as “PI”) is one of thephospholipids in cell membranes. In recent years it has become clearthat PI plays an important role also in intracellular signaltransduction. It is well recognized in the art that PI (4,5)bisphosphate (PI(4,5)P2 or PIP2) is degraded into diacylglycerol andinositol (1,4,5) triphosphate by phospholipase C to induce activation ofprotein kinase C and intracellular calcium mobilization, respectively[M. J. Berridge et al., Nature, 312, 315 (1984); Y. Nishizuka, Science,225, 1365 (1984)].

Phosphatidylinositol-3 kinase (“PI3K”) is an enzyme that phosphorylatesthe 3-position of the inositol ring of phosphatidylinositol [D. Whitmanet al., Nature, 332, 664 (1988)]. Pluralities of PI3K subtypes exist.Three major subtypes of PI3Ks have now been identified on the basis oftheir in vitro substrate specificity, and these three are designatedclass I (a & b), class 11, and class III [B. Vanhaesebroeck, Trend inBiol. Sci., 22, 267 (1997)].

The class Ia PI3K subtype has been most extensively investigated todate. Within the class Ia subtype there are three isoforms (a, b, & d)that exist as hetero dimers of a catalytic 110-kDa subunit andregulatory subunits of 50-85 kDa. The regulatory subunits contain SH2domains that bind to phosphorylated tyrosine residues within growthfactor receptors or adaptor molecules and thereby localize PI3K to theinner cell membrane. At the inner cell membrane PI3K converts PIP2 toPIP3 (phosphatidylinositol-3,4,5-trisphosphate) that serves to localizethe downstream effectors PDK1 and Akt to the inner cell membrane whereAkt activation occurs. Activated Akt mediates a diverse array of effectsincluding inhibition of apoptosis, cell cycle progression, response toinsulin signaling, and cell proliferation. Class Ia PI3K subtypes alsocontain Ras binding domains (RBD) that allow association with activatedRas providing another mechanism for PI3K membrane localization.Activated, oncogenic forms of growth factor receptors, Ras, and evenPI3K kinase have been shown to aberrantly elevate signaling in thePI3K/Akt/mTOR pathway resulting in cell transformation. As a centralcomponent of the PI3K/Akt/mTOR signaling pathway PI3K (particularly theclass Ia a isoform) has become a major therapeutic target in cancer drugdiscovery.

Substrates for class I PI3Ks are PI, PI(4)P and PI(4,5)P2, withPI(4,5)P2 being the most favored. Class I PI3Ks are further divided intotwo groups, class Ia and class Ib, because of their activation mechanismand associated regulatory subunits. The class Ib PI3K is p110γ that isactivated by interaction with G protein-coupled receptors. Interactionbetween p110γ and G protein-coupled receptors is mediated by regulatorysubunits of 110, 87, and 84 kDa.

PI and PI(4)P are the known substrates for class II PI3Ks; PI(4,5)P2 isnot a substrate for the enzymes of this class. Class II PI3Ks includePI3K C2α, C2β and C2γ isoforms, which contain C2 domains at the Cterminus, implying that their activity is regulated by calcium ions.

The substrate for class III PI3Ks is PI only. A mechanism for activationof the class III PI3Ks has not been clarified. Because each subtype hasits own mechanism for regulating activity, it is likely that activationmechanism(s) depend on stimuli specific to each respective class ofPI3K.

The compound PI103(3-(4-(4-morpholinyl)pyrido[3′,2′:4,5]furo[3,2-d]pyrimidin-2-yl)phenol)inhibits PI3Kα and PI3Kg as well as the mTOR enzymes with IC₅₀ values of2, 3, and 50-80 nM respectively. I.P. dosing in mice of this compound inhuman tumor xenograft models of cancer demonstrated activity against anumber of human tumor models, including the glioblastoma (PTEN nullU87MG), prostate (PC3), breast (MDA-MB-468 and MDA-MB-435) coloncarcinoma (HCT 116); and ovarian carcinoma (SKOV3 and IGROV-1); (Raynaudet al, Pharmacologic Characterization of a Potent Inhibitor of Class IPhosphatidylinositide 3-Kinases, Cancer Res. 2007 67: 5840-5850).

The compound ZSTK474(2-(2-difluoromethylbenzoimidazol-1-yl)-4,6-dimorpholino-1,3,5-triazine)inhibits PI3Kα and PI3Kg but not the mTOR enzymes with an IC₅₀ values of16, 4.6 and >10,000 nM respectively (Dexin Kong and Takao Yamori,ZSTK474 is an ATP-competitive inhibitor of class I phosphatidylinositol3 kinase isoforms, Cancer Science, 2007, 98:10 1638-1642). Chronic oraladministration of ZSTK474 in mouse human xenograft cancer models,completely inhibited growth which originated from a non-small-cell lungcancer (A549), a prostate cancer (PC-3), and a colon cancer (WiDr) at adose of 400 mg/kg. (Yaguchi et al, Antitumor Activity of ZSTK474, a NewPhosphatidylinositol 3-Kinase Inhibitor, J. Natl. Cancer Inst. 98:545-556).

The compound NVP-BEZ-235(2-methyl-2-(4-(3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)propanenitrile)inhibits both PI3Kα and PI3Kg as well as the mTOR enzymes with IC₅₀values 4, 5, and “nanomolar”. Testing in human tumor xenograft models ofcancer demonstrated activity against human tumor models of prostrate(PC-3) and glioblastoma (U-87) cancer. It entered clinical trials inDecember of 2006 (Verheijen, J. C. and Zask, A., Phosphatidylinositol3-kinase (PI3K) inhibitors as anticancer drugs, Drugs Fut. 2007, 32(6):537-547).

The compound SF-1126 (a prodrug form of LY-294002, which is2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one) is “a pan-PI3Kinhibitor”. It is active in preclinical mouse cancer models ofprostrate, breast, ovarian, lung, multiple myeloma, and brain cancers.(Verheijen, J. C. and Zask, A., Phosphatidylinositol 3-kinase (PI3K)inhibitors as anticancer drugs, Drugs Fut. 2007, 32(6): 537-547).

Although it seems clear that inhibition of the a isoform is essentialfor the antitumor activity of PI3K inhibitors, it is not clear whether amore selective inhibitor of a particular PI3K isoform may lead to fewerunwanted biological effects. It has recently been reported thatnon-PI3Kα class I isoforms (PI3Kβ, δ and γ) have the ability to induceoncogenic transformation of cells, suggesting that nonisoform-specificinhibitors may offer enhanced therapeutic potential over specificinhibitors.

Selectivity versus other related kinases is also an importantconsideration for the development of PI3K inhibitors. While selectiveinhibitors may be preferred in order to avoid unwanted side effects,there have been reports that inhibition of multiple targets in thePI3K/Akt pathway (e.g., PI3Kα and mTOR [mammalian target of rapamycin])may lead to greater efficacy. It is possible that lipid kinaseinhibitors may parallel protein kinase inhibitors in that nonselectiveinhibitors may also be brought forward to the clinic.

Mammalian Target of Rapamycin, mTOR, is a cell-signaling protein thatregulates the response of tumor cells to nutrients and growth factors,as well as controlling tumor blood supply through effects on VascularEndothelial Growth Factor, VEGF. Inhibitors of mTOR starve cancer cellsand shrink tumors by inhibiting the effect of mTOR. All mTOR inhibitorsbind to the mTOR kinase. This has at least two important effects. First,mTOR is a downstream mediator of the PI3K/Akt pathway. The PI3K/Aktpathway is thought to be over activated in numerous cancers and mayaccount for the widespread response from various cancers to mTORinhibitors. The over-activation of the upstream pathway would normallycause mTOR kinase to be over activated as well. However, in the presenceof mTOR inhibitors, this process is blocked. The blocking effectprevents mTOR from signaling to downstream pathways that control cellgrowth. Over-activation of the PI3K/Akt kinase pathway is frequentlyassociated with mutations in the PTEN gene, which is common in manycancers and may help predict what tumors will respond to mTORinhibitors. The second major effect of mTOR inhibition isanti-angiogenesis, via the lowering of VEGF levels.

In lab tests, certain chemotherapy agents were found to be moreeffective in the presence of mTOR inhibitors. George, J. N., et al.,Cancer Research, 61, 1527-1532, 2001. Additional lab results have shownthat some rhabdomyosarcoma cells die in the presence of mTOR inhibitors.

There are three mTOR inhibitors, which have progressed into clinicaltrials. These compounds are Wyeth's Torisel, also known as42-(3-hydroxy-2-(hydroxymethyl)-rapamycin 2-methylpropanoate, CCI-779 orTemsirolimus; Novartis' Everolimus, also known as42-O-(2-hydroxyethyl)-rapamycin, or RAD 001; and Ariad's AP23573 alsoknown as 42-(dimethylphopsinoyl)-rapamycin. The FDA has approved Toriselfor the treatment of advanced renal cell carcinoma. In addition, Toriselis active in a NOS/SCID xenograft mouse model of acute lymphoblasticleukemia [Teachey et al, Blood, 107(3), 1149-1155, 2006]. On Mar. 30,2009, the U.S. Food and Drug Administration (FDA) approved Everolimus(AFINITOR™) for the treatment of patients with advanced renal cellcarcinoma. AP23573 has been given orphan drug and fast-track status bythe FDA for treatment of soft-tissue and bone sarcomas.

The three mTOR inhibitors have non-linear, although reproduciblepharmacokinetic profiles. Mean area under the curve (AUC) values forthese drugs increase at a less than dose related way. The threecompounds are all semi-synthetic derivatives of the natural macrolideantibiotic rapamycin. It would be desirable to find fully syntheticcompounds, which inhibit mTOR that are more potent and exhibit improvedpharmacokinetic behaviors.

SUMMARY OF THE INVENTION

This invention provides compounds of formula I

wherein:

R¹ is

and R², R⁴, and R⁶⁻⁹ are defined below, and pharmaceutically acceptablesalts and esters thereof. These compounds are useful as inhibitors ofmTOR and PI3 kinases.

This invention further provides compositions containing one or more ofthe aforementioned compounds, which compositions may contain apharmaceutically acceptable carrier.

The present invention provides methods for making the compounds of theinvention, as described below. Methods of using the invention are alsoprovided, for example: a method for inhibiting mTOR, a method forinhibiting a PI3 kinase, and methods for treating various forms ofcancer.

DETAILED DESCRIPTION OF THE INVENTION

In one aspect, the present invention provides compounds of formula I

wherein:

R¹ is

wherein:

R⁶, R⁷, R⁸, R⁹ are each independently selected from the group consistingof a hydrogen atom, and a C₁-C₆alkyl optionally substituted withC₂-C₆alkenyl, C₄-C₆alkadienyl, C₂-C₆alkynyl or C₄-C₆alkadiynyl;

and one of R⁶ and R⁹, R⁶ and R⁸, or R⁷ and R⁸ are attached by a(CH₂)_(y), (CH₂—X—), or (CH₂—X—CH₂) linking group wherein one or twohydrogen atoms in the linking group may be independently replaced byC₁-C₆alkyl, (C₁-C₆alkyl)NH—, (C₁-C₆alkyl)₂N—, (C₆-C₁₄aryl)alkyl-O—,halo, 3-10 membered C₁-C₉heterocyclyl optionally substituted withC₁-C₆alkyl-, HO—, or H₂N—;

wherein any two hydrogen atoms on the same carbon atom of the linkinggroup can be replaced by an oxygen atom to form an oxo (═O) substituent,

y is 1, 2 or 3;

X is O, S(O)_(n), or NR¹⁰;

n is 0, 1 or 2;

the dashed line ----- represents an optional second bond;

R¹⁰ is selected from the group consisting of H, C₁-C₆alkyl,—SO₂(C₁-C₆alkyl), —COO(C₁-C₆alkyl), —CONH(C₁-C₆alkyl),—CON(C₁-C₆alkyl)₂, —CO(C₁-C₆alkyl), and —SO₂NHR¹¹;

R¹¹ is selected from the group consisting of H, C₁-C₆alkyl optionallysubstituted with OH, NR¹¹R¹¹ or a 3-7 membered C₁-C₆heterocyclyl,—CO(C₁-C₆alkyl), optionally substituted C₆-C₁₀aryl, and optionallysubstituted C₁-C₉heteroaryl;

R² is optionally substituted C₆-C₁₄aryl-NH—COR³, optionally substitutedC₁-C₉heteroaryl-NH—COR³, —CH═CH—C₆-C₁₀aryl-NH—COR³ or—CH═CH—C₁-C₉heteroaryl-NH—COR³;

R³ is OR⁵, NR⁵R⁵ or NHR⁵;

R⁵ is independently selected from the group consisting of C₁-C₆alkyl,C₃-C₆alkenyl, C₃-C₆alkynyl, optionally substituted C₆-C₁₀aryl,C₁-C₆haloalkyl, optionally substituted C₁-C₉heteroaryl,C₁-C₆hydroxylalkyl-, C₃-C₁₀saturated or unsaturated mono or bicyclicC₃-C₁₀cycloalkyl optionally substituted with OH, NR¹¹R¹¹ or 3-7 memberedC₁-C₆heterocyclyl, and 3-10 membered saturated or unsaturated mono orbicyclic C₁-C₉heterocyclyl, with the proviso that three-memberedcycloalkyl and heterocyclyl rings are saturated;

or two R⁵ groups taken together with the nitrogen atom to which they areattached form a 3 to 8 membered ring system optionally substituted withC₁-C₆alkyl, which ring system is saturated or unsaturated and has, inaddition to said nitrogen atom, 0 to 2 heteroatom ring members selectedfrom O, S, S(O), S(O)₂ and NR¹⁰;

R⁴ is selected from the group consisting of: a) C₁-C₆alkyl optionallysubstituted with: i) 3-10 membered C₁-C₉heterocyclyl optionallysubstituted with C₁-C₆alkyl-, ii) H₂N—, iii) (C₁-C₆alkyl)NH—, iv)(C₁-C₆alkyl)₂N—, v) NH(CH₂)_(a)N(C₁-C₆alkyl)₂ wherein a is 2, 3 or 4,and yl) CHO, b) C₃-C₆alkenyl, c) C₃-C₆alkynyl, d) —O—C₁-C₈alkyloptionally substituted with —O—C₁-C₈alkyl, e) —O—C₃-C₈alkenyl, f)—O—C₃-C₈alkynyl, g) saturated or unsaturated mono or bicyclicC₃-C₈cycloalkyl, and h) saturated or unsaturated mono or bicyclic—O—C₃-C₁₂cycloalkyl, all the above optionally substituted with OH,NR¹¹R¹¹ or a 3-7 membered C₁-C₆heterocyclyl optionally substituted withC₁-C₆alkyl-, provided that an OH or NR¹¹R¹¹ is not directly bonded to acarbon atom that is double- or triple-bonded to another carbon atom; i)—CH═CH—C₆-C₁₀aryl; j) —CH═CH—C₁-C₉heteroaryl; k) optionally substitutedC₆-C₁₀aryl; l) optionally substituted 5-10 membered C₁-C₉heteroarylattached to the triazine moiety via a carbon atom; m) 3-10 memberedsaturated or unsaturated mono or bicyclic C₁-C₉heterocyclyl attached tothe triazine moiety through a carbon or nitrogen atom and optionallysubstituted with from 1 to 3 substituents independently selected from:OH, NR¹¹R¹¹, C₁-C₆alkyl, (C₁-C₆alkyl)amido-, (C₁-C₆alkyl)C(O)—,(C₁-C₆alkoxy)carbonyl-, adamantyl, C₁-C₆hydroxylalkyl-, or a 3-7membered C₁-C₆heterocyclyl, with the proviso that 3 memberedheterocyclyl is saturated and attached to the triazine moiety through anitrogen atom, and 5 membered bicyclic heterocyclyl is saturated; n)optionally substituted —O—C₆-C₁₀aryl; o) optionally substituted—O—C₁-C₉heteroaryl; p) —O-(3-12 membered saturated or unsaturated monoor bicyclic)C₁-C₉heterocyclyl optionally substituted with(C₁-C₆alkoxy)carbonyl-, H₂NS(O)₂—, or C₁-C₆alkyl further optionallysubstituted with OH, NR¹¹R¹¹ or a 3-7 membered C₁-C₆heterocyclyl, withthe proviso that three membered heterocyclyl is saturated; q)—NHC₆-C₁₀aryl, r) —NHC₁-C₉heteroaryl, s) —NHNH₂, t) —NHNHC₁-C₆alkyl, u)—NHN(C₁-C₆alkyl)₂, v) —NHOH, w) —COOH, x) —COO—C₁-C₆alkyl, y)—CONR¹²R¹³, z) —NR¹²R¹³,

wherein Z is CH₂, O, S(O), or NR¹⁰;ee) halogen, ff) C₆-C₁₄aryl-S(O)₂—NH—, gg) R¹¹NHC(O)NH—O—, and hh)optionally substituted 5-membered monocyclic C₁-C₄heteroaryl attached tothe triazine moiety via a nitrogen atom;

R¹² and R¹³ are each independently selected from H, optionally mono ordisubstituted C₁-C₈alkyl, optionally substituted C₃-C₈alkenyl, andoptionally substituted C₃-C₈alkynyl, the optional substituents beingselected from C₁-C₆alkoxy, OH, NR¹¹R¹¹, and 3-7 memberedC₁-C₆heterocyclyl, provided that an OH or NR¹¹R¹¹ is not directly bondedto a carbon atom that is double- or triple-bonded to another carbonatom;

or R¹² and R¹³ taken together with the nitrogen atom to which they areattached form a 3 to 8 membered ring system optionally substituted withC₁-C₆alkyl, which ring system is saturated or

unsaturated and has, in addition to said nitrogen atom, 0 to 2heteroatom ring members selected from O, S(O)_(n) and NR¹⁰;

or R¹² and R¹³ taken together with the nitrogen atom to which they areattached form

-   -   wherein a and b are each independently —CH₂—, O, S, or NR¹⁰, and        x is 1-3;

C₁-C₉heteroaryl refers to a 5-10 membered aromatic ring system havingone or more rings and 1, 2, 3 or 4 ring members independently selectedfrom O, NR¹⁰, and S(O)_(n);

C₁-C₉heterocyclyl refers to a 3-10 membered ring system having one ormore rings and 1, 2, 3 or 4 ring members independently selected from O,NR¹⁰, and S(O)_(n); and

optionally substituted aryl and heteroaryl groups are unsubstituted orare substituted with 1 or 2 moieties selected from the group consistingof: a) C₁-C₆alkyl optionally substituted with OH, NH₂, NH(C₁-C₆alkyl),N(C₁-C₆alkyl)₂, —NH(CH₂)_(w)N(C₁-C₆alkyl)₂ wherein w is 2, 3 or 4, or3-10 membered C₁-C₉heterocyclyl optionally substituted with from 1 to 3independently selected C₁-C₆alkyl- substituents; b) halogen; c) hydroxy;d) NH₂; e) NO₂; f) SO₂NH₂; g) COOH; h) COO(C₁-C₆alkyl); i)NHCOO(C₁-C₆alkyl); j) NH(C₁-C₆alkyl); k) N(C₁-C₆alkyl)₂; I)C(O)NR^(a)R^(b), wherein R^(a) is H or C₁-C₆alkyl, and R^(b) is H,C₁-C₆alkyl, (C₆-C₁₄aryl)alkyl-, or (C₁-C₉heteroaryl)alkyl-; m) -Y-Q,wherein Y is: i) O, ii) NH, iii) N(C₁-C₆alkyl), iv) NHSO₂, v) SO₂NH, vi)NHCONH, vii) NHCON(C₁-C₆alkyl), viii) S(O)_(q), q is 0, 1 or 2,ix)-C(O)NH—, x) —C(O)N(CH₃)—, xi)-NHC(O)— xii) C(O), or xiii) absent,and Q is selected from: i) C₆-C₁₀aryl, optionally substituted with from1 to 3 substituents independently selected from: A) C₁-C₆alkoxy-optionally substituted with 1) H₂N—, 2) (C₁-C₆alkyl)amino-, 3)di(C₁-C₆alkyl)amino-, 4) C₁-C₉heterocyclyl- optionally substituted byC₁-C₆alkyl-, or 5) hydroxyl, B) (C₁-C₆alkoxy)carbonyl-, C)(C₁-C₆alkoxy)C(O)NH—, D) C₁-C₆alkyl- optionally substituted with 1)H₂N—, 2) (C₁-C₆alkyl)amino-, or 3) di(C₁-C₆alkyl)amino-, E)(C₁-C₆alkyl)amino-, F) di(C₁-C₆alkyl)amino-, G) (C₁-C₆alkyl)amido-optionally substituted with 1) H₂N—, 2) (C₁-C₆alkyl)amino-, or 3)di(C₁-C₆alkyl)amino-, H) (C₁-C₆alkyl)carboxyamido-, I)C₁-C₉heterocyclyl-optionally substituted by C₁-C₆alkyl- orC₁-C₆hydroxylalkyl-, J) heterocyclyl(C₁-C₆alkyl)- optionally substitutedby C₁-C₆alkyl-, K) halogen, L) hydroxyl, M) C₁-C₆hydroxylalkyl-, N)perfluoro(C₁-C₆)alkyl-, O) H₂N—, P) O₂N—, Q) H₂NSO₂—, R) HO₂C—, and S)NC—, ii) 5-10 membered C₁-C₉heteroaryl, optionally substituted with from1 to 3 substituents independently selected from: A)C₁-C₆alkoxy-optionally substituted with 1) H₂N—, 2) (C₁-C₆alkyl)amino-,3) di(C₁-C₆alkyl)amino-, 4) C₁-C₉heterocyclyl- optionally substituted byC₁-C₆alkyl-, or 5) hydroxyl, B) (C₁-C₆alkoxy)carbonyl-, C)(C₁-C₆alkoxy)C(O)NH—, D) C₁-C₆alkyl- optionally substituted with 1)H₂N—, 2) (C₁-C₆alkyl)amino-, or 3) di(C₁-C₆alkyl)amino-, E)(C₁-C₆alkyl)amino-, F) di(C₁-C₆alkyl)amino-, G)(C₁-C₆alkyl)amido-optionally substituted with 1) H₂N—, 2)(C₁-C₆alkyl)amino-, or 3) di(C₁-C₆alkyl)amino-, H)(C₁-C₆alkyl)carboxyamido-, I) C₁-C₉heterocyclyl- optionally substitutedby C₁-C₆alkyl- or C₁-C₆hydroxylalkyl-, J) heterocyclyl(C₁-C₆alkyl)-optionally substituted by C₁-C₆alkyl-, K) halogen, L) hydroxyl, M)C₁-C₆hydroxylalkyl-, N) perfluoro(C₁-C₆)alkyl-, O) H₂N—, P)O₂N—, Q)H₂NSO₂—, R) HO₂C—, and S) NC—, iii) 3-10 membered C₁-C₉heterocyclyl,optionally substituted with from 1 to 3 substituents independentlyselected from: A) C₁-C₆alkyl-, B) heterocyclyl(C₁-C₆alkyl)-, C)(C₆-C₁₄aryl)alkyl-, D) C₁-C₈acyl-, E) (C₁-C₆alkoxy)carbonyl-, F)(C₁-C₆alkyl)carboxyl-, G) halogen, H) C₁-C₆haloalkyl-, I) hydroxyl, J)C₁-C₆hydroxyalkyl-, K) H₂N—, L) (C₁-C₆alkyl)amino-, M)di(C₁-C₆alkyl)amino-, N) HO₂C—, O) (C₁-C₆alkoxy)carbonyl-, P)(C₁-C₆alkyl)carboxyl-, Q) (C₁-C₆alkyl)amido-, R) H₂NC(O)—, S)(C₁-C₆alkyl)carboxyamido-, T) 5-10 membered C₁-C₉heteroaryl, U)C₆-C₁₄ary, V) C₃-C₈cycloalkyl W) 3-10 membered C₁-C₉heterocyclyl, and X)—NO₂; iv) C₃-C₁₀cycloalkyl, v) C₁-C₆alkyl, vi) C₂-C₆alkenyl, vii)C₂-C₆alkynyl, viii) C₁-C₆hydroxyalkyl-, ix) (CH₂)_(v)O(C₁-C₆alkyl), x)(CH₂)_(v)NH₂, xi) (CH₂)_(v)NH(C₁-C₆alkyl), xii) (CH₂)_(v)N(C₁-C₆alkyl)₂,xiii) O(CH₂)_(v)N(C₁-C₆alkyl)₂, xiv) (CH₂)_(v)C₆-C₁₀aryl, xv) —CN, xvi)(CH₂)_(v) 5-10 membered C₁-C₉heteroaryl, xvii) (CH₂)_(v) 3-10 memberedC₁-C₉heterocyclyl, optionally substituted by C₁-C₆alkyl-, wherein v is1, 2, 3 or 4, and xviii) C₁-C₆ perfluoroalkyl-; and n) C(O)R^(c) whereinR^(c) is: i) H, ii) C₁-C₆alkyl, or iii) C₃-C₆cycloalkyl,

and pharmaceutically acceptable salts and esters thereof.

In some embodiments of the invention, R¹ and/or R⁴ is

and pharmaceutically acceptable salts or esters thereof.

In some embodiments of the invention, R¹ and/or R⁴ is

and pharmaceutically acceptable salts thereof.

In some embodiments of the invention, R¹ and/or R⁴ is

and pharmaceutically acceptable salts thereof.

In some embodiments of the invention, R¹ and/or R⁴ is independentlyselected from

In some embodiments R⁴ is

In some embodiments R⁴ is

In some embodiments R⁴ is

In some embodiments, R² is optionally substituted C₆-C₁₄aryl-NH—COR³; inothers R² is optionally substituted phenyl-NH—COR³.

In some embodiments, R³ is NHR⁵ or OR⁵. In some embodiments, R⁵ isoptionally substituted C₆-C₁₀aryl or C₁-C₉heteroaryl, such as pyridyl.In some embodiments, the C₁-C₉heteroaryl, is 4-pyridyl.

The following compounds exemplify illustrative compounds of Formula I:

-   1-{4-[4-morpholin-4-yl-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-phenylurea;-   1-(4-fluorophenyl)-3-{4-[4-morpholin-4-yl-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}urea;-   1-(4-methylphenyl)-3-{4-[4-morpholin-4-yl-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}urea;-   1-[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-yl-1,3,5-triazin-2-yl)phenyl]-3-methylurea;-   2-hydroxyethyl[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-yl-1,3,5-triazin-2-yl)phenyl]carbamate;-   1-[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(4-methylpiperazin-1-yl)phenyl]urea;-   1-[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-yl-1,3,5-triazin-2-yl)phenyl]-3-ethylurea;-   1-cyclopropyl-3-[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-yl-1,3,5-triazin-2-yl)phenyl]urea;-   1-[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-yl-1,3,5-triazin-2-yl)phenyl]-3-pyridin-4-ylurea;-   1-[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(hydroxymethyl)phenyl]urea;-   1-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;-   4-[({4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide;-   1-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea;-   1-(4-fluorophenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;-   1-[4-(hydroxymethyl)phenyl]-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;-   1-[4-(2-hydroxyethyl)phenyl]-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;-   2-(diethylamino)ethyl    4-[({4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzoate;-   1-(4-methylphenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;-   1-(4-cyanophenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;-   1-[4-(4-methylpiperazin-1-yl)phenyl]-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;-   1-isopropyl-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;-   1-(2-hydroxyethyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;-   1-{4-[4-morpholin-4-yl-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea;-   1-{4-[4-morpholin-4-yl-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;-   t-butyl    2-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-chloro-1,3,5-triazin-2-ylamino)ethylcarbamate;-   1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(piperidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea;-   1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea;-   1-{4-[4-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy)-6-morpholin-4-yl-[1,3,5]triazin-2-yl]-phenyl}-3-pyridin-4-yl-urea;-   4-(3-{4-[4-(8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy)-6-morpholin-4-yl-[1,3,5]triazin-2-yl]-phenyl}-ureido)-benzamide;-   tert-butyl    4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-pyridin-4-ylureido)phenyl)-1,3,5-triazin-2-yl)piperazine-1-carboxylate;-   1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea;-   1-{4-[4-(4-methylpiperazin-1-yl)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;-   1-{4-[4-(4-benzylpiperazin-1-yl)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;-   1-(4-{4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-[4-(pyridin-3-ylmethyl)piperazin-1-yl]-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea;-   1-{4-[4-(4-acetylpiperazin-1-yl)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;-   1-(4-{4-[4-(N,N-dimethylglycyl)piperazin-1-yl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea;-   1-{4-[4-(4-isonicotinoylpiperazin-1-yl)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;-   methyl    4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-{4-[(pyridin-4-ylcarbamoyl)-amino]phenyl}-1,3,5-triazin-2-yl]piperazine-1-carboxylate;-   1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-oxopiperidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea;-   1-{4-[4-(4-hydroxypiperidin-1-yl)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;-   1-(4-{4-[4-(benzylamino)piperidin-1-yl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea;-   1-(4-{4-[4-(methylamino)piperidin-1-yl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea;-   1-(4-{4-[4-(ethylamino)piperidin-1-yl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea;-   1-{4-[4-(4-{[2-(dimethylamino)ethyl]amino}piperidin-1-yl)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;-   1-{4-[4-(4-morpholin-4-ylpiperidin-1-yl)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;-   1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea;-   1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(2-hydroxyethylamino)piperidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea;-   1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(2-morpholinoethylamino)piperidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea;-   methyl    2-(1-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-pyridin-4-ylureido)phenyl)-1,3,5-triazin-2-yl)piperidin-4-ylamino)acetate;-   2-(1-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-pyridin-4-ylureido)phenyl)-1,3,5-triazin-2-yl)piperidin-4-ylamino)acetamide    tert-butyl    2-(1-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-pyridin-4-ylureido)phenyl)-1,3,5-triazin-2-yl)piperidin-4-ylamino)acetate;-   2-(1-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-pyridin-4-ylureido)phenyl)-1,3,5-triazin-2-yl)piperidin-4-ylamino)acetic    acid;-   1-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-(2-piperidin-1-ylethoxy)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;-   methyl(4-{4-[4-({[4-(4-methylpiperazin-1-yl)phenyl]carbamoyl}amino)phenyl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)carbamate;-   1-cyclopropyl-3-(4-{4-[4-({[4-(4-methylpiperazin-1-yl)phenyl]carbamoyl}amino)phenyl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)urea;-   N′,N′″-{[6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazine-2,4-diyl]di-4,1-phenylene}bis{1-[4-(4-methylpiperazin-1-yl)phenyl]urea};-   1-[4-(4-methylpiperazin-1-yl)phenyl]-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-{4-[(pyridin-4ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl]phenyl}urea;-   1-(4-{4-[(2-aminoethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-3-ylurea;-   1-{4-[4-anilino-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea;-   1-(4-{4-[(2-hydroxyethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-3-ylurea;-   1-{4-[4-(azetidin-3-ylamino)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea;-   1-(4-{4-[(2-morpholin-4-ylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-3-ylurea;-   1-(4-{4-[(3-aminopropyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-3-ylurea;-   1-(4-{4-[(4-cyclopentylpiperazin-1-yl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-3-ylurea;-   1-{4-[4-isopropoxy-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;-   1-{4-[4-isopropoxy-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-[4-(4-methylpiperazin-1-yl)phenyl]urea;-   1-{4-[4-chloro-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;-   1-(4-{4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-[(piperidin-4-ylmethyl)amino]-1,3,5-triazin-2-yl}phenyl)-3-pyridin-3-ylurea;-   1-(4-{4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-[(2-piperidin-4-ylethyl)amino]-1,3,5-triazin-2-yl}phenyl)-3-pyridin-3-ylurea;-   1-{4-[4-(3-methylimidazolidin-1-yl)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea;-   1-{4-[4-(3-methyltetrahydropyrimidin-1(2H)-yl)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea;-   1-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-(2-piperidin-1-ylethoxy)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea;-   1-(4-{4-[2-methoxy-1-(methoxymethyl)ethoxy]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea;-   1-(4-{4-[2-methoxy-1-(methoxymethyl)ethoxy]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-[4-(4-methylpiperazin-1-yl)phenyl]urea;-   2-hydroxyethyl    (4-{4-[2-methoxy-1-(methoxymethyl)ethoxy]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)carbamate;-   1-(4-{4-[2-methoxy-1-(methoxymethyl)ethoxy]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-methylurea;-   1-cyclopropyl-3-(4-{4-[2-methoxy-1-(methoxymethyl)ethoxy]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)urea;-   1-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-(piperidin-3-ylmethoxy)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea;-   1-{4-[4-(4-aminobutoxy)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea;-   1-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-(2-piperidin-4-ylethoxy)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea;-   1-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-(piperidin-4-ylmethoxy)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea;-   1-(4-{4-morpholin-4-yl-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea;-   1-{4-[4-(methylamino)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea;-   1-{4-[4-(ethylamino)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea;-   1-{4-[4-(dimethylamino)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea;-   1-{4-[4-(isopropylamino)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea;-   1-{4-[4-(diethylamino)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea;-   1-(diethylcarbamoyl)-4-[({4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]pyridinium;-   1-(4-{4-[ethyl(methyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-3-ylurea;-   1-{4-[4-(sec-butylamino)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea;-   1-{4-[4-{[2-hydroxy-1-(hydroxymethyl)ethyl]amino}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea;-   1-(4-{4-[bis(2-hydroxyethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-3-ylurea;-   1-(4-{4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-3-ylurea;-   1-{4-[4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea;-   1-(4-{4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-[(4-piperazin-1-ylphenyl)amino]-1,3,5-triazin-2-yl}phenyl)-3-pyridin-3-ylurea;-   1-(4-{4-morpholin-4-yl-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-1,3,5-triazin-2-yl}phenyl)-3-{4-[(4-pyrrolidin-1-ylpiperidin-1-yl)carbonyl]phenyl}urea;-   1-methyl-3-(4-{4-[(1-methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)urea;-   1-cyclopropyl-3-(4-{4-[(1-methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)urea;-   1-(2-hydroxyethyl)-3-(4-{4-[(1-methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)urea;-   1-(4-{4-[(1-methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea;-   1-(4-{4-[(1-methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]urea;-   1-(4-{4-[(1-methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-[4-(4-methylpiperazin-1-yl)phenyl]urea;-   1-{4-[(2,2-dimethylhydrazino)carbonyl]phenyl}-3-(4-{4-[(1-methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)urea;-   4-{[(4-{4-[(1-methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)carbamoyl]amino}-N-pyrrolidin-1-ylbenzamide;-   1-{4-[2-(dimethylamino)ethoxy]phenyl}-3-(4-{4-[(1-methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)urea;-   1-[4-(hydroxymethyl)phenyl]-3-(4-{4-[(1-methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)urea;-   1-[4-(2-hydroxyethyl)phenyl]-3-(4-{4-[(1-methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)urea;-   1-[4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-yl-1,3,5-triazin-2-yl)phenyl]-3-pyridin-4-ylurea;-   1-[4-(4-methylpiperazin-1-yl)phenyl]-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;-   1-(4-acetylphenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;-   1-methyl-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)-1,3,5-triazin-2-yl]phenyl}urea;-   1-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea;-   1-(4-ethenylphenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;-   1-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;-   tert-butyl(1R,4R)-5-(4-morpholin-4-yl-6-{4-[(pyridin-4-ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate;-   tert-butyl    (1R,4R)-5-[4-(4-{[(4-acetylphenyl)carbamoyl]amino}-phenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate;-   1-(4-{4-[(2-methoxyethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-3-ylurea;-   1-{4-[4-{[(1S)-2-hydroxy-1-methylethyl]amino}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea;-   1-{4-[4-{[(1R)-2-hydroxy-1-methylethyl]amino}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea;-   1-(4-{4-[(2-hydroxy-1,1-dimethylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-3-ylurea;-   1-{4-[4-(tert-butylamino)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea;-   1-[4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-yl-1,3,5-triazin-2-yl)phenyl]-3-(4-piperazin-1-ylphenyl)urea;-   1-[4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(4-methylpiperazin-1-yl)phenyl]urea;-   1-{4-[2-(dimethylamino)ethoxy]phenyl}-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;-   1-{4-[4-(6-hydroxy-3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;-   tert-butyl-7-(4-morpholin-4-yl-6-{4-[(pyridin-4-ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate;-   1-{4-[4-(6,8-dioxa-3-azabicyclo[3.2.1]oct-3-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;-   1-[4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-yl-1,3,5-triazin-2-yl)phenyl]-3-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}urea;-   N-[4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-yl-1,3,5-triazin-2-yl)phenyl]piperazine-1-carboxamide;-   1-[4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(hydroxymethyl)phenyl]urea;-   1-[4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-yl-1,3,5-triazin-2-yl)phenyl]-3-{4-[(methylamino)methyl]phenyl}urea;-   1-{4-[2-(dimethylamino)ethoxy]phenyl}-3-[4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-yl-1,3,5-triazin-2-yl)phenyl]urea;-   1-{4-[4-morpholin-4-yl-6-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;-   1-{4-[4-(7-methyl-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;-   1-{4-[4-(7-acetyl-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;-   1-(4-{4-[7-(methylsulfonyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea;-   tert-butyl-(1R,4R)-5-{4-[4-({[4-(1-hydroxyethyl)phenyl]carbamoyl}amino)phenyl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate;-   1-[4-(4-methylpiperazin-1-yl)phenyl]-3-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}urea;-   1-{4-[4,6-di-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-1,3,5-triazin-2-yl]phenyl}-3-[4-(4-methylpiperazin-1-yl)phenyl]urea;-   1-{4-[4,6-di-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-1,3,5-triazin-2-yl]phenyl}-3-(4-piperazin-1-ylphenyl)urea;-   1-{4-[4,6-di-(1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-1,3,5-triazin-2-yl]phenyl}-3-[4-(4-methylpiperazin-1-yl)phenyl]urea;-   1-(2-fluoroethyl)-3-{4-[4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}urea;-   1-cyclopropyl-3-{4-[4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}urea;-   1-methyl-3-{4-[4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}urea;-   4-[({4-[4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide;-   1-{4-[4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-phenylurea;-   1-methyl-3-(4-{4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-[(4-piperazin-1-ylphenyl)amino]-1,3,5-triazin-2-yl}phenyl)urea;-   1-cyclopropyl-3-(4-{4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-[(4-piperazin-1-ylphenyl)amino]-1,3,5-triazin-2-yl}phenyl)urea;-   1-(2-fluoroethyl)-3-(4-{4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-[(4-piperazin-1-ylphenyl)amino]-1,3,5-triazin-2-yl}phenyl)urea;-   1-(2-hydroxyethyl)-3-(4-{4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-[(4-piperazin-1-ylphenyl)amino]-1,3,5-triazin-2-yl}phenyl)urea;-   4-{[(4-{4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-[(4-piperazin-1-ylphenyl)amino]-1,3,5-triazin-2-yl}phenyl)carbamoyl]amino}benzamide;-   1-(4-{4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-[(4-piperazin-1-ylphenyl)amino]-1,3,5-triazin-2-yl}phenyl)-3-phenylurea;-   1-methyl-3-{4-[4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}urea;-   1-cyclopropyl-3-{4-[4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}urea;-   1-(2-fluoroethyl)-3-{4-[4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}urea;-   4-[({4-[4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-yl]phenyl}carbamoyl)amino]benzamide;-   1-{4-[4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-phenylurea;-   1-(2,3′-bipyridin-4-yl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;-   1-(4-{4-[(2R,5S)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea;-   1-(4-{4-[(2R,5S)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl}phenyl)-3-[4-(4-methylpiperazin-1-yl)phenyl]urea;-   1-(6-chloropyridin-3-yl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;-   N-[4-({[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)phenyl]-N2,N2-dimethylglycinnamide;-   N-[4-({[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)phenyl]-2-pyrrolidin-1-ylacetamide;-   1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(piperazin-1-yl)phenylamino)-1,3,5-triazin-2-yl)phenyl)-3-methylurea;-   1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(piperazin-1-yl)phenylamino)-1,3,5-triazin-2-yl)phenyl)-3-cyclopropylurea;-   1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(piperazin-1-yl)phenylamino)-1,3,5-triazin-2-yl)phenyl)-3-(2-fluoroethyl)urea;-   1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(piperazin-1-yl)phenylamino)-1,3,5-triazin-2-yl)phenyl)-3-(2-hydroxyethyl)urea;-   4-(3-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(piperazin-1-yl)phenylamino)-1,3,5-triazin-2-yl)phenyl)ureido)benzamide;-   1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(piperazin-1-yl)phenylamino)-1,3,5-triazin-2-yl)phenyl)-3-phenylurea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(piperidin-4-ylamino)-1,3,5-triazin-2-yl)phenyl)-3-ethylurea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(piperidin-4-ylamino)-1,3,5-triazin-2-yl)phenyl)-3-ethylurea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(piperidin-4-ylamino)-1,3,5-triazin-2-yl)phenyl)-3-ethylurea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(piperidin-4-ylamino)-1,3,5-triazin-2-yl)phenyl)-3-ethylurea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(piperidin-4-ylamino)-1,3,5-triazin-2-yl)phenyl)-3-ethylurea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(piperidin-4-ylamino)-1,3,5-triazin-2-yl)phenyl)-3-ethylurea;-   1-(4-(4,6-di(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(piperazin-1-ylmethyl)phenyl)urea;-   1-(4-(4,6-di(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-((dimethylamino)methyl)phenyl)urea;-   1-(4-(aminomethyl)phenyl)-3-(4-(4,6-di(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)urea;-   1-(4-(4,6-di(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(pyrrolidin-1-ylmethyl)phenyl)urea;-   1-(4-(4,6-di(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)urea;-   1-(4-(4,6-di(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)urea;-   1-(4-(4,6-di(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-hydroxyethoxy)phenyl)urea;-   N-(4-(3-(4-(4,6-di(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)ureido)phenyl)-2-(dimethylamino)acetamide;-   N-(4-(3-(4-(4,6-di(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)ureido)phenyl)-2-(4-methylpiperazin-1-yl)acetamide;-   N-(4-(3-(4-(4,6-di(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)ureido)phenyl)-2-(pyrrolidin-1-yl)acetamide;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-3-yl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-triazin-2-yl)phenyl)-3-(4-((4-methylpiperazin-1-yl)methyl)phenyl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(piperazin-1-ylmethyl)phenyl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-triazin-2-yl)phenyl)-3-(4-((dimethylamino)methyl)phenyl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(aminomethyl)phenyl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(pyrrolidin-1-ylmethyl)phenyl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-(dimethylamino)ethoxy)phenyl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-triazin-2-yl)phenyl)-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(piperazin-1-yl)phenyl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(dimethylamino)piperidin-1-yl)phenyl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropyl(methyl)amino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropyl(methyl)amino)-1,3,5-triazin-2-yl)phenyl)-3-(4-((dimethylamino)methyl)phenyl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropyl(methyl)amino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-(dimethylamino)ethoxy)phenyl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-thiomorpholino-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-3-yl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-thiomorpholino-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-thiomorpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-thiomorpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-((dimethylamino)methyl)phenyl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-thiomorpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-(dimethylamino)ethoxy)phenyl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(3,6-dihydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(3,6-dihydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-(dimethylamino)ethoxy)phenyl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-((dimethylamino)methyl)phenyl)urea;-   1-(4-(4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea;-   1-(4-(4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-3-yl)urea;-   1-(4-(4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea;-   1-(4-(4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-((4-methylpiperazin-1-yl)methyl)phenyl)urea;-   1-(4-(4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(pyrrolidin-1-ylmethyl)phenyl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-3-yl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(pyrrolidin-1-ylmethyl)phenyl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-(dimethylamino)ethoxy)phenyl)urea;-   1-[4-(4-methylpiperazin-1-yl)phenyl]-3-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-(1-oxidothiomorpholin-4-yl)-1,3,5-triazin-2-yl]phenyl}urea-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-ethylpiperazin-1-yl)phenyl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazin-1-yl)phenyl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-cyclopropylpiperazin-1-yl)phenyl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(dimethylamino)piperidin-1-yl)phenyl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazine-1-carbonyl)phenyl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazine-1-carbonyl)phenyl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-ethylpiperazin-1-yl)phenyl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazin-1-yl)phenyl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-cyclopropylpiperazin-1-yl)phenyl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(dimethylamino)piperidin-1-yl)phenyl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazine-1-carbonyl)phenyl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazine-1-carbonyl)phenyl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)urea;-   4-(3-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)ureido)benzamide;-   4-(3-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)ureido)-N,N-dimethylbenzamide;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(pyrrolidine-1-carbonyl)phenyl)urea;-   4-(3-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)ureido)-N-(2-(dimethylamino)ethyl)benzamide;-   4-(3-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)ureido)-N-(2-(methylamino)ethyl)benzamide;-   4-(3-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)ureido)-N-(2-(dimethylamino)ethyl)-N-methylbenzamide;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(morpholine-4-carbonyl)phenyl)urea;-   1-(4-(2-aminoethylamino)phenyl)-3-(4-(4,6-di(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)urea;-   4-[({4-[4-{4-[(methylcarbamoyl)amino]phenyl}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide;-   3-[({4-[4-{4-[(methylcarbamoyl)amino]phenyl}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide;-   1-methyl-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-{4-[(pyridin-4-ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl]phenyl}urea;-   1-{4-[4-(5-hydroxy-3-oxa-7-azabicyclo[4.1.1]oct-7-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;-   1-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridazin-4-ylurea;-   N-[4-({[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)phenyl]-2-(4-methylpiperazin-1-yl)acetamide;-   1-(4-{[(3S)-3-(dimethylamino)pyrrolidin-1-yl]carbonyl}phenyl)-3-{4-[4-morpholin-;-   4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;-   1-(4-{[(3S)-3-(dimethylamino)pyrrolidin-1-yl]carbonyl}phenyl)-3-{4-[4-morpholin-;-   4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;-   N-[4-({[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)phenyl]-2-(4-methylpiperazin-1-yl)acetamide;-   1-(4-{4-[(2R,5S)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea;-   1-(4-{4-[(2R,5S)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-[4-(4-methylpiperazin-1-yl)phenyl]urea;-   1-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;-   4-[({4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide;-   1-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea;-   1-(4-fluorophenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;-   1-[4-(hydroxymethyl)phenyl]-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;-   1-[4-(2-hydroxyethyl)phenyl]-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;-   2-(diethylamino)ethyl    4-[({4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzoate;-   1-(4-methylphenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;-   1-(4-cyanophenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;-   1-[4-(4-methylpiperazin-1-yl)phenyl]-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;-   1-isopropyl-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;-   1-(2-hydroxyethyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;-   1-{4-[4-(3-hydroxy-8-azabicyclo[3.2.1]oct-8-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-phenylurea;-   methyl    4-[({4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzoate;-   N-[2-(dimethylamino)ethyl]-4-[({4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide;-   N,N-dimethyl-4-[({4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide;-   N-methyl-4-[({4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide;-   1-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;-   N-[2-(dimethylamino)ethyl]-N-methyl-4-[({4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide;-   N-(2-hydroxyethyl)-4-[({4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide;-   N-[3-(dimethylamino)propyl]-4-[({4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide;-   N-methyl-N-[2-(methylamino)ethyl]-4-[({4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide;-   N-(2-morpholin-4-ylethyl)-4-[({4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide;-   1-{4-[(3,5-dimethylpiperazin-1-yl)carbonyl]phenyl}-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;-   1-(diethylcarbamoyl)-4-[({4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]pyridinium;-   1-[4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-yl-1,3,5-triazin-2-yl)phenyl]-3-pyridin-4-ylurea;-   1-(4-acetylphenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;-   1-(4-ethenylphenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;-   1-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;-   1-{4-[2-(dimethylamino)ethoxy]phenyl}-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;-   1-{4-[4-(6,8-dioxa-3-azabicyclo[3.2.1]oct-3-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;-   tert-butyl    7-(4-morpholin-4-yl-6-{4-[(pyridin-4-ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate;-   1-{4-[4-morpholin-4-yl-6-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;-   1-{4-[4-(7-methyl-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;-   1-{4-[4-(7-acetyl-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;-   1-(4-{4-[7-(methylsulfonyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea;-   1-(2-chloropyridin-4-yl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;-   1-(2,3′-bipyridin-4-yl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;-   1-(6-chloropyridin-3-yl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;-   1,3-bis{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;-   1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;-   N-[2-(4-methylpiperazin-1-yl)ethyl]-4-[({4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide;-   1-{4-[(4-isopropylpiperazin-1-yl)carbonyl]phenyl}-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;-   1-{4-[(4-cyclopentylpiperazin-1-yl)carbonyl]phenyl}-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;-   1-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}-3-[4-(piperazin-1-ylcarbonyl)phenyl]urea;-   1-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}-3-{4-[(4-morpholin-4-ylpiperidin-1-yl)carbonyl]phenyl}urea;-   4-[({4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]-N-(2-pyrrolidin-1-ylethyl)benzamide;-   4-[({4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]-N-(2-piperidin-1-ylethyl)benzamide;-   1-[4-(1,4′-bipiperidin-1′-ylcarbonyl)phenyl]-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;-   1-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}-3-{4-[(4-pyrrolidin-1-ylpiperidin-1-yl)carbonyl]phenyl}urea;-   1-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}-3-[4-(thiomorpholin-4-ylcarbonyl)phenyl]urea;-   1-[4-(morpholin-4-ylcarbonyl)phenyl]-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;-   4-[({4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzoic    acid;-   1-{4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;-   1-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;-   1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-{4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}urea;-   N-[2-(dimethylamino)ethyl]-4-[({4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]-N-methylbenzamide;-   1-{4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}urea;-   methyl    4-[({4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzoate;-   4-[({4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzoic    acid;-   1-{4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-[4-(piperazin-1-ylcarbonyl)phenyl]urea;-   1-{4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-{4-[(4-isopropylpiperazin-1-yl)carbonyl]phenyl}urea;-   4-[({4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]-N-(2-pyrrolidin-1-ylethyl)benzamide;-   4-[({4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]-N-(2-piperidin-1-ylethyl)benzamide;-   1-{4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-{4-[(4-pyrrolidin-1-ylpiperidin-1-yl)carbonyl]phenyl}urea;-   1-[4-(1,4′-bipiperidin-1′-ylcarbonyl)phenyl]-3-{4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}urea;-   4-[({4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]-N-(2-pyridin-2-ylethyl)benzamide;-   4-[({4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]-N-(2-pyridin-4-ylethyl)benzamide;-   1-{4-[4-morpholin-4-yl-6-(3-oxa-9-azabicyclo[3.3.1]non-9-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;-   1-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-3-{4-[4-morpholin-4-yl-6-(3-oxa-9-azabicyclo[3.3.1]non-9-yl)-1,3,5-triazin-2-yl]phenyl}urea;-   1-{4-[4-morpholin-4-yl-6-(3-oxa-9-azabicyclo[3.3.1]non-9-yl)-1,3,5-triazin-2-yl]phenyl}-3-[4-(piperazin-1-ylcarbonyl)phenyl]urea;-   1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-9-azabicyclo[3.3.1]non-9-yl)-1,3,5-triazin-2-yl]phenyl}urea;-   N-[2-(dimethylamino)ethyl]-N-methyl-4-[({4-[4-morpholin-4-yl-6-(3-oxa-9-azabicyclo[3.3.1]non-9-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide;-   N-[2-(dimethylamino)ethyl]-4-[({4-[4-morpholin-4-yl-6-(3-oxa-9-azabicyclo[35.3.]non-9-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide;-   N-(2-methoxyethyl)-4-[({4-[4-morpholin-4-yl-6-(3-oxa-9-azabicyclo[3.3.1]non-9-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide;-   4-[({4-[4-morpholin-4-yl-6-(3-oxa-9-azabicyclo[3.3.1]non-9-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]-N-(2-pyrrolidin-1-ylethyl)benzamide;-   4-[({4-[4-morpholin-4-yl-6-(3-oxa-9-azabicyclo[3.3.1]non-9-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]-N-(2-piperidin-1-ylethyl)benzamide;-   1-{4-[4-morpholin-4-yl-6-(3-oxa-9-azabicyclo[3.3.1]non-9-yl)-1,3,5-triazin-2-yl]phenyl}-3-{4-[(4-pyrrolidin-1-ylpiperidin-1-yl)carbonyl]phenyl}urea;-   N-[2-(1-methylpyrrolidin-2-yl)ethyl]-4-[({4-[4-morpholin-4-yl-6-(3-oxa-9-azabicyclo[3.3.1]non-9-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide;-   N-methyl-N-[2-(methylamino)ethyl]-4-[({4-[4-morpholin-4-yl-6-(3-oxa-9-azabicyclo[3.3.1]non-9-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide;-   1-{4-[(4-ethylpiperazin-1-yl)carbonyl]phenyl}-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;-   1-{4-[(4-ethylpiperazin-1-yl)carbonyl]phenyl}-3-{4-[4-morpholin-4-yl-6-(3-oxa-9-azabicyclo[3.3.1]non-9-yl)-1,3,5-triazin-2-yl]phenyl}urea;-   1-(4-{[4-(1-methylethyl)piperazin-1-yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-9-azabicyclo[3.3.1]non-9-yl)-1,3,5-triazin-2-yl]phenyl}urea;-   1-{4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-{4-[(4-ethylpiperazin-1-yl)carbonyl]phenyl}urea;-   1-{4-[4-morpholin-4-yl-6-(2-oxa-5-azabicyclo[2.2.2]oct-5-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;-   1-(1,3-dimethyl-1H-pyrazol-5-yl)-3-{4-[4-morpholin-4-yl-6-(2-oxa-5-azabicyclo[2.2.2]oct-5-yl)-1,3,5-triazin-2-yl]phenyl}urea;-   1-{4-[4-morpholin-4-yl-6-(2-oxa-5-azabicyclo[2.2.2]oct-5-yl)-1,3,5-triazin-2-yl]phenyl}-3-(1H-pyrazol-3-yl)urea;-   1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6-(2-oxa-5-azabicyclo[2.2.2]oct-5-yl)-1,3,5-triazin-2-yl]phenyl}urea;-   1-(4-{[4-(1-methylethyl)piperazin-1-yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6-(2-oxa-5-azabicyclo[2.2.2]oct-5-yl)-1,3,5-triazin-2-yl]phenyl}urea;-   1-{4-[(4-ethylpiperazin-1-yl)carbonyl]phenyl}-3-{4-[4-morpholin-4-yl-6-(2-oxa-5-azabicyclo[2.2.2]oct-5-yl)-1,3,5-triazin-2-yl]phenyl}urea;-   1-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-3-{4-[4-morpholin-4-yl-6-(2-oxa-5-azabicyclo[2.2.2]oct-5-yl)-1,3,5-triazin-2-yl]phenyl}urea;-   1-{4-[4-morpholin-4-yl-6-(2-oxa-5-azabicyclo[2.2.2]oct-5-yl)-1,3,5-triazin-2-yl]phenyl}-3-[4-(piperazin-1-ylcarbonyl)phenyl]urea;-   N-[2-(dimethylamino)ethyl]-4-[({4-[4-morpholin-4-yl-6-(2-oxa-5-azabicyclo[2.2.2]oct-5-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide;-   N-[2-(dimethylamino)ethyl]-N-methyl-4-[({4-[4-morpholin-4-yl-6-(2-oxa-5-azabicyclo[2.2.2]oct-5-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide;-   1-(4-{4-[(6S)-6-hydroxy-3-oxa-8-azabicyclo[3.2.1]oct-8-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea;-   1-(4-{4-[6-(benzyloxy)-3-oxa-8-azabicyclo[3.2.1]oct-8-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea;-   1-(4-{4-[(6R)-6-hydroxy-3-oxa-8-azabicyclo[3.2.1]oct-8-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea;-   1-(4-{4-[(6R)-6-(benzyloxy)-3-oxa-8-azabicyclo[3.2.1]oct-8-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea;-   1-{4-[(1,1-dioxidothiomorpholin-4-yl)carbonyl]phenyl}-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;-   1-[4-(4,6-di-3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(4-methylpiperazin-1-yl)phenyl]urea;-   1-(4-{[(3S)-3-(dimethylamino)pyrrolidin-1-yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;-   1-(4-{[(3R)-3-(dimethylamino)pyrrolidin-1-yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;-   1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazin-1-yl)phenyl)urea;-   1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-ethylpiperazin-1-yl)phenyl)urea;-   1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(cyclopropylmethyl)piperazin-1-yl)phenyl)urea;-   1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-cyclopropylpiperazin-1-yl)phenyl)urea;-   1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(quinuclidin-4-yl)phenyl)urea;-   1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(dimethylamino)piperidin-1-yl)phenyl)urea;-   1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)urea;-   1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazine-1-carbonyl)phenyl)urea;-   1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazine-1-carbonyl)phenyl)urea;-   1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(dimethylamino)piperidine-1-carbonyl)phenyl)urea;-   1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-ethylpiperazine-1-carbonyl)phenyl)urea;-   1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-cyclopropylpiperazine-1-carbonyl)phenyl)urea;-   1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(cyclopropylmethyl)piperazine-1-carbonyl)phenyl)urea;-   1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)urea;-   1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(dimethylamino)piperidin-1-yl)phenyl)urea;-   1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(quinuclidin-4-yl)phenyl)urea;-   1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-cyclopropylpiperazin-1-yl)phenyl)urea;-   1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(cyclopropylmethyl)piperazin-1-yl)phenyl)urea;-   1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-ethylpiperazin-1-yl)phenyl)urea;-   1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazin-1-yl)phenyl)urea;-   1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea;-   1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazine-1-carbonyl)phenyl)urea;-   1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazine-1-carbonyl)phenyl)urea;-   1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(dimethylamino)piperidine-1-carbonyl)phenyl)urea;-   1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-ethylpiperazine-1-carbonyl)phenyl)urea;-   1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-cyclopropylpiperazine-1-carbonyl)phenyl)urea;-   1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(cyclopropylmethyl)piperazine-1-carbonyl)phenyl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazin-1-yl)phenyl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-ethylpiperazin-1-yl)phenyl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(cyclopropylmethyl)piperazin-1-yl)phenyl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-cyclopropylpiperazin-1-yl)phenyl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(quinuclidin-4-yl)phenyl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(dimethylamino)piperidin-1-yl)phenyl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazine-1-carbonyl)phenyl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazine-1-carbonyl)phenyl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(dimethylamino)piperidine-1-carbonyl)phenyl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-ethylpiperazine-1-carbonyl)phenyl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-cyclopropylpiperazine-1-carbonyl)phenyl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(cyclopropylmethyl)piperazine-1-carbonyl)phenyl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(dimethylamino)piperidin-1-yl)phenyl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(quinuclidin-4-yl)phenyl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-cyclopropylpiperazin-1-yl)phenyl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(cyclopropylmethyl)piperazin-1-yl)phenyl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-ethylpiperazin-1-yl)phenyl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazin-1-yl)phenyl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazine-1-carbonyl)phenyl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazine-1-carbonyl)phenyl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(dimethylamino)piperidine-1-carbonyl)phenyl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-ethylpiperazine-1-carbonyl)phenyl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-cyclopropylpiperazine-1-carbonyl)phenyl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(cyclopropylmethyl)piperazine-1-carbonyl)phenyl)urea;-   1-(4-(4,6-bis((1S,5S,6S)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea;-   1-(4-(4,6-bis((1S,5S,6S)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazin-1-yl)phenyl)urea;-   1-(4-(4,6-bis((1S,5S,6S)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-ethylpiperazin-1-yl)phenyl)urea;-   1-(4-(4,6-bis((1S,5S,6S)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(dimethylamino)piperidin-1-yl)phenyl)urea;-   1-(4-(4,6-bis((1S,5S,6S)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(quinuclidin-4-yl)phenyl)urea;-   1-(4-(4,6-bis((1S,5S,6S)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-cyclopropylpiperazin-1-yl)phenyl)urea;-   1-(4-(4,6-bis((1S,5S,6S)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(cyclopropylmethyl)piperazin-1-yl)phenyl)urea;-   1-(4-(4,6-bis((1S,5S,6S)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea;-   1-(4-(4,6-bis((1S,5S,6S)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-3-yl)urea;-   1-(4-(4,6-bis((1S,5S,6S)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazine-1-carbonyl)phenyl)urea;-   1-(4-(4,6-bis((1S,5S,6S)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-ethylpiperazine-1-carbonyl)phenyl)urea;-   1-(4-(4,6-bis((1S,5S,6S)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazine-1-carbonyl)phenyl)urea;-   1-(4-(4,6-bis((1S,5S,6S)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(dimethylamino)piperidine-1-carbonyl)phenyl)urea;-   1-(4-(4,6-bis((1S,5S,6S)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-cyclopropylpiperazine-1-carbonyl)phenyl)urea;-   1-(4-(4,6-bis((1S,5S,6S)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(cyclopropylmethyl)piperazine-1-carbonyl)phenyl)urea;-   1-(4-(4,6-bis((1S,5S,6R)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea;-   1-(4-(4,6-bis((1S,5S,6R)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazin-1-yl)phenyl)urea;-   1-(4-(4,6-bis((1S,5S,6R)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-ethylpiperazin-1-yl)phenyl)urea;-   1-(4-(4,6-bis((1S,5S,6R)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(dimethylamino)piperidin-1-yl)phenyl)urea;-   1-(4-(4,6-bis((1S,5S,6R)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(quinuclidin-4-yl)phenyl)urea;-   1-(4-(4,6-bis((1S,5S,6R)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-cyclopropylpiperazin-1-yl)phenyl)urea;-   1-(4-(4,6-bis((1S,5S,6R)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(cyclopropylmethyl)piperazin-1-yl)phenyl)urea;-   1-(4-(4,6-bis((1S,5S,6R)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea;-   1-(4-(4,6-bis((1S,5S,6R)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-3-yl)urea;-   1-(4-(4,6-bis((1S,5S,6R)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazine-1-carbonyl)phenyl)urea;-   1-(4-(4,6-bis((1S,5S,6R)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-ethylpiperazine-1-carbonyl)phenyl)urea;-   1-(4-(4,6-bis((1S,5S,6R)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazine-1-carbonyl)phenyl)urea;-   1-(4-(4,6-bis((1S,5S,6R)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(dimethylamino)piperidine-1-carbonyl)phenyl)urea;-   1-(4-(4,6-bis((1S,5S,6R)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-cyclopropylpiperazine-1-carbonyl)phenyl)urea;-   1-(4-(4,6-bis((1S,5S,6R)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(cyclopropylmethyl)piperazine-1-carbonyl)phenyl)urea;-   1-(4-(4-((1S,5S,6R)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((1S,5S,6S)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea;-   1-(4-(4,6-bis(6,6-difluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea;-   1-(4-(4,6-bis(6,6-difluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazin-1-yl)phenyl)urea;-   1-(4-(4,6-bis(6,6-difluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-ethylpiperazin-1-yl)phenyl)urea;-   1-(4-(4,6-bis(6,6-difluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(dimethylamino)piperidin-1-yl)phenyl)urea;-   1-(4-(4,6-bis(6,6-difluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(quinuclidin-4-yl)phenyl)urea;-   1-(4-(4,6-bis(6,6-difluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-cyclopropylpiperazin-1-yl)phenyl)urea;-   1-(4-(4,6-bis(6,6-difluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(cyclopropylmethyl)piperazin-1-yl)phenyl)urea;-   1-(4-(4,6-bis(6,6-difluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea;-   1-(4-(4,6-bis(6,6-difluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-3-yl)urea;-   1-(4-(4,6-bis(6,6-difluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazine-1-carbonyl)phenyl)urea;-   1-(4-(4,6-bis(6,6-difluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-ethylpiperazine-1-carbonyl)phenyl)urea;-   1-(4-(4,6-bis(6,6-difluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazine-1-carbonyl)phenyl)urea;-   1-(4-(4,6-bis(6,6-difluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(dimethylamino)piperidine-1-carbonyl)phenyl)urea;-   1-(4-(4,6-bis(6,6-difluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-cyclopropylpiperazine-1-carbonyl)phenyl)urea;-   1-(4-(4,6-bis(6,6-difluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(cyclopropylmethyl)piperazine-1-carbonyl)phenyl)urea;-   1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(pyrimidin-5-yl)urea;-   1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(pyridazinyl-4-yl)urea;-   1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea;-   1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-3-yl)urea;-   1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(pyridazin-4-yl)urea;-   1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(pyrimidin-5-yl)urea;-   4-(3-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)ureido)benzamide;-   4-(3-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)ureido)-N-(2-(dimethylamino)ethyl)benzamide;-   4-(3-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)ureido)-N-(2-(methylamino)ethyl)benzamide;-   1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-((R)-3-(dimethylamino)pyrrolidine-1-carbonyl)phenyl)urea;-   1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(piperazine-1-carbonyl)phenyl)urea;-   1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazine-1-carbonyl)phenyl)urea;-   1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-ethylpiperazine-1-carbonyl)phenyl)urea;-   1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazine-1-carbonyl)phenyl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-3-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-3-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-3-yl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-3-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(pyridazin-4-yl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-3-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(pyrimidin-5-yl)urea;-   4-(3-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-3-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)ureido)benzamide;-   4-(3-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-3-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)ureido)-N-(2-(dimethylamino)ethyl)benzamide;-   4-(3-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-3-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)ureido)-N-(2-(methylamino)ethyl)benzamide;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-3-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-((R)-3-(dimethylamino)pyrrolidine-1-carbonyl)phenyl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-3-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(piperazine-1-carbonyl)phenyl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-3-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazine-1-carbonyl)phenyl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-3-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-ethylpiperazine-1-carbonyl)phenyl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-3-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazine-1-carbonyl)phenyl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-acetylphenyl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-(dimethylamino)acetyl)phenyl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-morpholinoacetyl)phenyl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-hydroxyacetyl)phenyl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(methoxymethyl)phenyl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-methoxyethyl)phenyl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(1-hydroxyethyl)phenyl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-hydroxypropan-2-yl)phenyl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-hydroxypropyl)phenyl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-hydroxy-2-methylpropyl)phenyl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(dimethylamino)piperidine-1-carbonyl)phenyl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-acetylphenyl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-(dimethylamino)acetyl)phenyl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-morpholinoacetyl)phenyl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-hydroxyacetyl)phenyl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(methoxymethyl)phenyl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-methoxyethyl)phenyl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(1-hydroxyethyl)phenyl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-hydroxypropan-2-yl)phenyl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-hydroxypropyl)phenyl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-hydroxy-2-methylpropyl)phenyl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(dimethylamino)piperidine-1-carbonyl)phenyl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-3-yl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(piperazin-1-yl)phenyl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-cyanophenyl)urea;-   4-(3-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)ureido)-N-methylbenzamide;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(6-(4-methylpiperazine-1-carbonyl)pyridin-3-yl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-((dimethylamino)methyl)phenyl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(piperazin-1-yl)phenyl)urea;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-cyanophenyl)urea;-   4-(3-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)ureido)benzamide;-   4-(3-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)ureido)-N,N-dimethylbenzamide;-   4-(3-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)ureido)-N-methylbenzamide;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(pyrrolidine-1-carbonyl)phenyl)urea;-   4-(3-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)ureido)-N-(2-(dimethylamino)ethyl)benzamide;-   4-(3-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)ureido)-N-(2-(methylamino)ethyl)benzamide;-   1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(6-(4-methylpiperazine-1-carbonyl)pyridin-3-yl)urea;-   1-(4-{[(3S)-3-(dimethylamino)pyrrolidin-1-yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;-   1-(4-{[(3R)-3-(dimethylamino)pyrrolidin-1-yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;-   1-(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea;-   1-(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl}phenyl)-3-(4-{[4-(propan-2-yl)piperazin-1-yl]carbonyl}phenyl)urea;-   N-[2-(dimethylamino)ethyl]-N-methyl-4-{[(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl}phenyl)carbamoyl]amino}benzamide;-   4-{[(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl}phenyl)carbamoyl]amino}benzoic    acid;-   1-(4-{[(3R)-3-(dimethylamino)pyrrolidin-1-yl]carbonyl}phenyl)-3-(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl}phenyl)urea;-   1-(4-{[(3S)-3-(dimethylamino)pyrrolidin-1-yl]carbonyl}phenyl)-3-(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl}phenyl)urea;-   1-(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl}phenyl)-3-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}urea;-   1-{4-[(4-ethylpiperazin-1-yl)carbonyl]phenyl}-3-(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl}phenyl)urea;-   1-{4-[4-(morpholin-4-yl)-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}-3-{4-[(3,3,4-trimethylpiperazin-1-yl)carbonyl]phenyl}urea;    and-   1-(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl}phenyl)-3-[4-(piperazin-1-ylcarbonyl)phenyl]urea.

The invention also includes the following compounds, not of Formula I,made by the process illustrated in Scheme 13, which have mTOR inhibitingactivity:

-   8,8′-(6-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-1,3,5-triazine-2,4-diyl)bis(3-oxa-8-azabicyclo[3.2.1]octane);-   8-(4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)-3-oxa-8-azabicyclo[3.2.1]octane;-   8-(4-morpholino-6-(2-(trifluoromethyl)-1H-benzo[d]imidazol-1-yl)-1,3,5-triazin-2-yl)-3-oxa-8-azabicyclo[3.2.1]octane;-   8,8′-(6-(2-(trifluoromethyl)-1H-benzo[d]imidazol-1-yl)-1,3,5-triazine-2,4-diyl)bis(3-oxa-8-azabicyclo[3.2.1]octane);-   5,5′-(6-(2-(trifluoromethyl)-1H-benzo[d]imidazol-1-yl)-1,3,5-triazine-2,4-diyl)bis(2-oxa-5-azabicyclo[2.2.1]heptane);-   5,5′-(6-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-1,3,5-triazine-2,4-diyl)bis(2-oxa-5-azabicyclo[2.2.1]heptane);-   5-(4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane;-   5-(4-morpholino-6-(2-(trifluoromethyl)-1H-benzo[d]imidazol-1-yl)-1,3,5-triazin-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane;-   8,8′-(6-(2-(fluoromethyl)-1H-benzo[d]imidazol-1-yl)-1,3,5-triazine-2,4-diyl)bis(3-oxa-8-azabicyclo[3.2.1]octane);-   5,5′-(6-(2-(fluoromethyl)-1H-benzo[d]imidazol-1-yl)-1,3,5-triazine-2,4-diyl)bis(2-oxa-5-azabicyclo[2.2.1]heptane);-   8-(4-(2-(fluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)-3-oxa-8-azabicyclo[3.2.1]octane;-   5-(4-(2-(fluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane;-   8,8′-(6-(2-methyl-1H-benzo[d]imidazol-1-yl)-1,3,5-triazine-2,4-diyl)bis(3-oxa-8-azabicyclo[3.2.1]octane);-   5,5′-(6-(2-methyl-1H-benzo[d]imidazol-1-yl)-1,3,5-triazine-2,4-diyl)bis(2-oxa-5-azabicyclo[2.2.1]heptane);-   8-(4-(2-methyl-1H-benzo[d]imidazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)-3-oxa-8-azabicyclo[3.2.1]octane;-   5-(4-(2-methyl-1H-benzo[d]imidazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane;-   8,8′-(6-(1H-benzo[d]imidazol-1-yl)-1,3,5-triazine-2,4-diyl)bis(3-oxa-8-azabicyclo[3.2.1]octane);-   5,5′-(6-(1H-benzo[d]imidazol-1-yl)-1,3,5-triazine-2,4-diyl)bis(2-oxa-5-azabicyclo[2.2.1]heptane);-   8-(4-(1H-benzo[d]imidazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)-3-oxa-8-azabicyclo[3.2.1]octane;-   5-(4-(1H-benzo[d]imidazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane;-   3,3′-(6-(1H-benzo[d]imidazol-1-yl)-1,3,5-triazine-2,4-diyl)bis(8-oxa-3-azabicyclo[3.2.1]octane);-   3-(4-(1H-benzo[d]imidazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane;-   3,3′-(6-(2-methyl-1H-benzo[d]imidazol-1-yl)-1,3,5-triazine-2,4-diyl)bis(8-oxa-3-azabicyclo[3.2.1]octane);-   3-(4-(2-methyl-1H-benzo[d]imidazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane;-   3,3′-(6-(2-(fluoromethyl)-1H-benzo[d]imidazol-1-yl)-1,3,5-triazine-2,4-diyl)bis(8-oxa-3-azabicyclo[3.2.1]octane);-   3-(4-(2-(fluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane;-   3,3′-(6-(2-(trifluoromethyl)-1H-benzo[d]imidazol-1-yl)-1,3,5-triazine-2,4-diyl)bis(8-oxa-3-azabicyclo[3.2.1]octane);-   3-(4-morpholino-6-(2-(trifluoromethyl)-1H-benzo[d]imidazol-1-yl)-1,3,5-triazin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane;-   8-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-1,3,5-triazin-2-yl)-3-oxa-8-azabicyclo[3.2.1]octane;-   3-(4-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-6-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-1,3,5-triazin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane;    and-   8-(4-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-6-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-1,3,5-triazin-2-yl)-3-oxa-8-azabicyclo[3.2.1]octane.

The invention also includes pharmaceutical compositions comprising acompound of formula I and a pharmaceutically acceptable carrier. Theinvention includes a compound of formula I when provided as apharmaceutically acceptable prodrug, hydrated salt, such aspharmaceutically acceptable salt, or mixtures thereof.

In other aspects, the invention provides that the pharmaceuticallyacceptable carrier suitable for oral administration and the compositioncomprises an oral dosage form.

In other aspects, the invention provides a composition comprising acompound of Formula I, a second compound selected from the groupconsisting of a topoisomerase I inhibitor, a MEK 1/2 inhibitor, a HSP90inhibitor, procarbazine, dacarbazine, gemcitabine, capecitabine,methotrexate, taxol, taxotere, mercaptopurine, thioguanine, hydroxyurea,cytarabine, cyclophosphamide, ifosfamide, nitrosoureas, cisplatin,carboplatin, mitomycin, dacarbazine, procarbizine, etoposide,teniposide, campathecins, bleomycin, doxorubicin, idarubicin,daunorubicin, dactinomycin, plicamycin, mitoxantrone, L-asparaginase,doxorubicin, epirubicin, 5-fluorouracil, docetaxel, paclitaxel,leucovorin, levamisole, irinotecan, estramustine, etoposide, nitrogenmustards, BCNU, carmustine, lomustine, vinblastine, vincristine,vinorelbine, cisplatin, carboplatin, oxaliplatin, imatinib mesylate,Avastin (bevacizumab), hexamethylmelamine, topotecan, tyrosine kinaseinhibitors, tyrphostins, herbimycin A, genistein, erbstatin,hydroxyzine, glatiramer acetate, interferon beta-1a, interferon beta-1b,natalizumab and lavendustin A; and a pharmaceutically acceptablecarrier.

In other aspects, the second compound is Avastin.

In other aspects, the invention provides a method of treating aPI3K-related disorder, comprising administering to a mammal in needthereof a compound of Formula I in an amount effective to treat aPI3K-related disorder.

In other aspects, the PI3K-related disorder is selected from restenosis,atherosclerosis, bone disorders, arthritis, diabetic retinopathy,psoriasis, benign prostatic hypertrophy, atherosclerosis, inflammation,angiogenesis, immunological disorders, pancreatitis, kidney disease, andcancer.

In other aspects, the PI3K-related disorder is cancer.

In other aspects, the cancer is selected from the group consisting ofleukemia, skin cancer, bladder cancer, breast cancer, uterus cancer,ovary cancer, prostate cancer, lung cancer, colon cancer, pancreascancer, renal cancer, gastric cancer, and brain cancer.

In other aspects, the invention provides a method of treating anmTOR-related disorder, comprising administering to a mammal in needthereof a compound of Formula I in an amount effective to treat anmTOR-related disorder.

In other aspects, the mTOR-related disorder is selected from restenosis,atherosclerosis, bone disorders, arthritis, diabetic retinopathy,psoriasis, benign prostatic hypertrophy, atherosclerosis, inflammation,angiogenesis, immunological disorders, pancreatitis, kidney disease, andcancer.

In other aspects, the mTOR-related disorder is cancer.

In other aspects, the cancer is selected from the group consisting ofleukemia, skin cancer, bladder cancer, breast cancer, uterus cancer,ovary cancer, prostate cancer, lung cancer, colon cancer, pancreascancer, renal cancer, gastric cancer, and brain cancer.

In other aspects, the invention provides a method of treating ahSMG-1-related disorder, comprising administering to a mammal in needthereof a compound of Formula I in an amount effective to treat ahSMG-1-related disorder.

In other aspects, the hSMG-1-related disorder is selected fromrestenosis, atherosclerosis, bone disorders, arthritis, diabeticretinopathy, psoriasis, benign prostatic hypertrophy, atherosclerosis,inflammation, angiogenesis, immunological disorders, pancreatitis,kidney disease, and cancer.

In other aspects, the hSMG-1-related disorder is cancer.

In other aspects, the cancer is selected from the group consisting ofleukemia, skin cancer, bladder cancer, breast cancer, uterus cancer,ovary cancer, prostate cancer, lung cancer, colon cancer, pancreascancer, renal cancer, gastric cancer, and brain cancer.

In other aspects, the invention provides a method of treating advancedrenal cell carcinoma, comprising administering to a mammal in needthereof a compound of Formula I in an amount effective to treat advancedrenal cell carcinoma.

In other aspects, the invention provides a method of treating acutelymphoblastic leukemia, comprising administering to a mammal in needthereof a compound of Formula I in an amount effective to treat acutelymphoblastic leukemia.

In other aspects, the invention provides a method of treating acutemalignant melanoma, comprising administering to a mammal in need thereofa compound of Formula I in an amount effective to treat malignantmelanoma.

In other aspects, the invention provides a method of treatingsoft-tissue or bone sarcoma, comprising administering to a mammal inneed thereof a compound of Formula I in an amount effective to treatsoft-tissue or bone sarcoma.

In other aspects, the invention provides a method of treating a cancerselected from the group consisting of leukemia, skin cancer, bladdercancer, breast cancer, uterus cancer, ovary cancer, prostate cancer,lung cancer, colon cancer, pancreas cancer, renal cancer, gastriccancer, and brain cancer comprising administering to a mammal in needthereof a composition comprising a compound of Formula I; a secondcompound selected from the group consisting of a topoisomerase Iinhibitor, a MEK 1/2 inhibitor, a HSP90 inhibitor, procarbazine,dacarbazine, gemcitabine, capecitabine, methotrexate, taxol, taxotere,mercaptopurine, thioguanine, hydroxyurea, cytarabine, cyclophosphamide,ifosfamide, nitrosoureas, cisplatin, carboplatin, mitomycin,dacarbazine, procarbizine, etoposide, teniposide, campathecins,bleomycin, doxorubicin, idarubicin, daunorubicin, dactinomycin,plicamycin, mitoxantrone, L-asparaginase, doxorubicin, epirubicin,5-fluorouracil, docetaxel, paclitaxel, leucovorin, levamisole,irinotecan, estramustine, etoposide, nitrogen mustards, BCNU,carmustine, lomustine, vinblastine, vincristine, vinorelbine, cisplatin,carboplatin, oxaliplatin, imatinib mesylate, Avastin (bevacizumab),hexamethylmelamine, topotecan, tyrosine kinase inhibitors, tyrphostins,herbimycin A, genistein, erbstatin, and lavendustin A; and apharmaceutically acceptable carrier. in an amount effective to treat thecancer.

In other aspects, the invention provides a method of inhibiting mTOR ina subject, comprising administering to a subject in need thereof acompound of Formula I in an amount effective to inhibit mTOR.

In other aspects, the invention provides a method of inhibiting PI3K ina subject, comprising administering to a subject in need thereof acompound of Formula I in an amount effective to inhibit PI3K.

In other aspects, the invention provides a method of inhibiting hSMG-1in a subject, comprising administering to a subject in need thereof acompound of Formula I in an amount effective to inhibit hSMG-1.

In other aspects, the invention provides a method of inhibiting mTOR,PI3K, and hSMG-1 together in a subject, comprising administering to asubject in need thereof a compound of Formula I in an amount effectiveto inhibit mTOR, PI3K, and hSMG-1.

In another aspect, the invention provides a method of synthesizingcompounds of the Formula I, which are:

said method comprising reacting 2,4,6-trichloro[1,3,5]triazine with

to form the intermediate dichlorotriazine compound

The method of synthesizing compounds of the Formula I further comprisingreacting the intermediate dichlorotriazine compound with

to form the intermediate compound

The method of synthesizing compounds of the Formula I further comprisingreacting the intermediate dichlorotriazine compound with

to form the intermediate compound

wherein each R⁶, R⁷, R⁸ and R⁹ is independently selected and definedaccording to formula I.

The method of synthesizing compounds of the Formula I wherein thereacting moiety

is independently selected from

Procedures used to synthesize the compounds of the present invention aredescribed in Schemes 1-12 and are illustrated in the examples.Reasonable variations of the described procedures are intended to bewithin the scope of the present invention:

Compounds of the present inventions were prepared by a multi-stepsequence as depicted in Scheme 1. One chlorine atom at a time wasselectively replaced at different temperatures. The commerciallyavailable cyanuric acid chloride 1 was reacted with morpholine orsubstituted morpholine derivatives at −10° C. to give the monomorpholine derivative 2. This pivotal intermediate 2 can be reacted withdifferent nucleophiles. In this present invention, intermediates 2 werereacted with different amines and alcohols to give 3 and 5 respectively.The third chlorine atom in intermediates 3 and 5 was replaced with4-aminoaryl and aminoheteroaryl boronic acid in the presence of(Ph₃)₄P(Pd)/Na₂CO₃/DME/Reflux or microwave condition to yield 4 and 8respectively. The amino group was converted to the urea derivatives bydifferent two procedures depending upon the availability of the startingmaterial. Some of the examples reported here were transformed into theurea derivative by reacting 4 or 8 with an appropriately substitutedisocyanate derivative. Many of the urea derivatives reported here wereprepared by reacting intermediates 4 or 8 with triphosgene/Et₃N and anappropriately substituted primary amine derivative. The correspondingcarbamate derivatives were prepared by reacting intermediates 4 or 8with an appropriately substituted chloroformate reagents. Theintermediates 2 were also used to prepare derivatives of 6, where in Ris a alkyl, alkene, alkyne, aryl or heteroaryl. Reacting 6 with theappropriately substituted alkyl introduced alkyl or cycloalkyl groups inintermediate 6 or cycloalkyl magnesium bromide or the correspondingappropriately substituted organo-zinc reagent. Alkenes can be introducedin compound 6 by a Pd catalyzed appropriately substituted vinyl tinderivatives. Similarly, aryl or heteroaryl substituents can beintroduced either by reacting 6 with the corresponding boronic acid(Suzuki coupling) or aryl or heteroaryl magnesium bromide. Alkynes canbe introduced by reacting compound 6 with an appropriately substitutealkyne and Pd(0). The alkyne and the alkene introduced can also befunctionally converted into other derivatives such as alkyl, alcohol andamine moieties. Detailed procedures are described in the experimentalsection for each derivative prepared.

Certain compounds of the invention were prepared by the methods outlinedin Scheme 2.

Compounds of the invention were also prepared according to the methodillustrated in Scheme 3.

appropriate amine as shown in Scheme 4.

The 4-(alkoxy)aniline intermediates were prepared from4-fluoronitrobenzene and the appropriate alcohol as shown in Scheme 5.

The thiomorpholine and bis morpholine compounds were prepared from2,4-dichloro-6-(4-nitrophenyl)-1,3,5-triazine and the appropriatemorpholine and thiomorpholine reagents as shown in Scheme 6.

The dihydropyran and tetrahydropyran compounds were prepared from2,4-dichloro-6-(4-nitrophenyl)-1,3,5-triazine,tributyl(3,6-dihydro-2H-pyran-4-yl)stannane, and the appropriatemorpholine as shown in Scheme 7.

The (4-aminophenyl)(piperazin-1-yl)methanone intermediates were preparedfrom 4-nitrobenzoyl chloride and the appropriate amine as shown inScheme 8.

The1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-ureacompounds were prepared from2,4-dichloro-6-(4-nitrophenyl)-1,3,5-triazine, (R)-3-methylmorpholine,3-oxa-8-azabicyclo[3.2.1]octane-hydrochloride, and the appropriate amineas shown in Scheme 9.

The preparation of both the (6S′) and (6R′) isomers of tert-butyl6-hydroxy-3-oxa-8-azabicyclo[3.2.1]octane-8-carboxylate from tert-butyl1H-pyrrole-1-carboxylate is shown in Scheme 10.

The (6S′)-tert-butyl6-amino-3-oxa-8-azabicyclo[3.2.1]octane-8-carboxylate and(6R′)-tert-butyl 6-fluoro-6-(alkyl, aryl, orheteroaryl)-3-oxa-8-azabicyclo[3.2.1]octane-8-carboxylate compoundscould be prepared from tert-butyl6-oxo-3-oxa-8-azabicyclo[3.2.1]octane-8-carboxylate (Scheme 10) and theappropriate amine or Grignard reagent as shown in Scheme 11.

Compounds of formula I can be prepared from cyanuric chloride as shownin Scheme 12.

(6-(1H-benzo[d]imidazol-1-yl)-1,3,5-triazine compounds can be preparedfrom cyanuric chloride as shown in Scheme 13. Cyanuric chloride istreated with one or two equivalents of bridged morpholine in aproticsolvent in the presence of base to give dichlorotriazine orchlorotriazine, respectively. The chlorotriazine is treated withbenzoimidazole in aprotic solvent in the presence of base to give thebenzoimidazole triazine. The dichlorotriazine is treated with amorpholine in aprotic solvent in the presence of base followed bybenzoimidazole in aprotic solvent in the presence of base to give thebenzoimidazole triazine.

DEFINITIONS

The following definitions are used in connection with the compounds ofthe present invention unless the context indicates otherwise. Ingeneral, the number of carbon atoms present in a given group isdesignated “C_(x)-C_(y)” where x and y are the lower and upper limits,respectively. For example, a group designated as “C₁-C₆” contains from 1to 6 carbon atoms. The carbon number as used in the definitions hereinrefers to carbon backbone and carbon branching, but does not includecarbon atoms of the substituents, such as alkoxy substitutions and thelike. Unless indicated otherwise, the nomenclature of substituents thatare not explicitly defined herein are arrived at by naming from left toright the terminal portion of the functionality followed by the adjacentfunctionality toward the point of attachment. For example, thesubstituent “arylalkyloxycabonyl” refers to the group(C₆-C₁₄aryl)-(C₁-C₆alkyl)-O—C(O)—. Terms not defined herein have themeaning commonly attributed to them by those skilled in the art.

“Acyl-” refers to a group having a straight, branched, or cyclicconfiguration or a combination thereof, attached to the parent structurethrough a carbonyl functionality. Such groups may be saturated orunsaturated, aliphatic or aromatic, and carbocyclic or heterocyclic.Examples of a C₁-C₈acyl- group include acetyl-, benzoyl-, nicotinoyl-,propionyl-, isobutyryl-, oxalyl-, and the like. Lower-acyl refers toacyl groups containing one to four carbons. An acyl group can beunsubstituted or substituted with one or more of the following groups:halogen, H₂N—, (C₁-C₆alkyl)amino-, di(C₁-C₆alkyl)amino-,(C₁-C₆alkyl)C(O)N(C₁-C₃alkyl)-, (C₁-C₆alkyl)carboxyamido-, HC(O)NH—,H₂NC(O)—, (C₁-C₆alkyl)NHC(O)—, di(C₁-C₆alkyl)NC(O)—, —CN, hydroxyl,C₁-C₆alkoxy-, C₁-C₆alkyl-, HO₂C—, (C₁-C₆alkoxy)carbonyl-,(C₁-C₆alkyl)C(O)—, C₆-C₁₄aryl-, C₁-C₉heteroaryl-, or C₃-C₈cycloalkyl-.

“Alkyl” refers to a hydrocarbon chain that may be a straight chain orbranched chain, containing the indicated number of carbon atoms, forexample, a C₁-C₁₂alkyl group may have from 1 to 12 (inclusive) carbonatoms in it. Examples of C₁-C₆alkyl groups include, but are not limitedto, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl,sec-butyl, tert-butyl, isopentyl, neopentyl, and isohexyl. Examples ofC₁-C₈alkyl groups include, but are not limited to, methyl, propyl,pentyl, hexyl, heptyl, 3-methylhex-1-yl, 2,3-dimethylpent-2-yl,3-ethylpent-1-yl, octyl, 2-methylhept-2-yl, 2,3-dimethylhex-1-yl, and2,3,3-trimethylpent-1-yl. An alkyl group can be unsubstituted orsubstituted with one or more groups, including: halogen, —NH₂,(C₁-C₆alkyl)N—, (C₁-C₆alkyl)(C₁-C₆alkyl)N—,—N(C₁-C₃alkyl)C(O)(C₁-C₆alkyl), —NHC(O)(C₁-C₆alkyl), —NHC(O)H, —C(O)NH₂,—C(O)NH(C₁-C₆alkyl), —C(O)N(C₁-C₆alkyl)(C₁-C₆alkyl), —CN, hydroxyl,C₁-C₆alkoxy, C₁-C₆alkyl, —C(O)OH, —C(O)O(C₁-C₆alkyl), —C(O)(C₁-C₆alkyl),C₆-C₁₄aryl, C₁-C₉heteroaryl, C₃-C₈cycloalkyl, C₁-C₆haloalkyl-,C₁-C₆-aminoalkyl-, —OC(O)(C₁-C₆alkyl), C₁-C₆-carboxyamidoalkyl-, and—NO₂.

“Alkadienyl” refer to a straight or branched chain unsaturatedhydrocarbon containing at least two double bonds, and either may existin the E or Z conformation. Examples of a C₄-C₆alkadienyl group include,but are not limited to, buta-1,3-dienyl, buta-2,3-dienyl, isoprenyl,penta-1,3-dienyl, and penta-2,4-dien-2-yl.

“Alkadiynyl” refer to a straight or branched chain unsaturatedhydrocarbon containing at least two triple bonds. Examples of aC₄-C₆alkadiynyl group include, but are not limited to, buta-1,3-diynyl,buta-2,3-diynyl, penta-1,3-diynyl, and penta-2,4-diynyl.

“Alkenyl” refer to a straight or branched chain unsaturated hydrocarboncontaining at least one double bond, and may exist in the E or Zconformation. Examples of a C₂-C₈alkenyl group include, but are notlimited to, ethylene, propylene, 1-butylene, 2-butylene, isobutylene,sec-butylene, 1-pentene, 2-pentene, isopentene, 1-hexene, 2-hexene,3-hexene, isohexene, 1-heptene, 2-heptene, 3-heptene, 1-octene,2-octene, 3-octene, and 4-octene. Examples of a C₂-C₆alkenyl groupinclude, but are not limited to, ethylene, propylene, 1-butylene,2-butylene, isobutylene, sec-butylene, 1-pentene, 2-pentene, isopentene,1-hexene, 2-hexene, 3-hexene, and isohexene. Examples of a C₃-C₈alkenylgroup include, but are not limited to, propylene, 1-butylene,2-butylene, isobutylene, sec-butylene, 1-pentene, 2-pentene, isopentene,1-hexene, 2-hexene, 3-hexene, isohexene, 1-heptene, 2-heptene,3-heptene, 1-octene, 2-octene, 3-octene, and 4-octene. Examples of aC₃-C₆alkenyl group include, but are not limited to, prop-2-enyl,but-3-enyl, but-2-enyl, 2-methylallyl, pent-4-enyl, and hex-5-enyl. Analkenyl group can be unsubstituted or substituted with one or moregroups, including: halogen, —NH₂, (C₁-C₆alkyl)N—,(C₁-C₆alkyl)(C₁-C₆alkyl)N—, —N(C₁-C₃alkyl)C(O)(C₁-C₆alkyl),—NHC(O)(C₁-C₆alkyl), —NHC(O)H, —C(O)NH₂, —C(O)NH(C₁-C₆alkyl),—C(O)N(C₁-C₆alkyl)(C₁-C₆alkyl), —CN, hydroxyl, C₁-C₆alkoxy, C₁-C₆alkyl,—C(O)OH, —C(O)O(C₁-C₆alkyl), —C(O)(C₁-C₆alkyl), C₆-C₁₄aryl,C₁-C₉heteroaryl, and C₃-C₈cycloalkyl.

“Alkynyl” refers to a straight or branched chain unsaturated hydrocarboncontaining at least one triple bond. Examples of a C₂-C₆alkynyl groupinclude, but are not limited to, acetylene, propyne, 1-butyne, 2-butyne,isobutyne, sec-butyne, 1-pentyne, 2-pentyne, isopentyne, 1-hexyne,2-hexyne, 3-hexyne, and isohexyne. Examples of a C₃-C₆alkynyl groupinclude, but are not limited to, prop-2-ynyl, but-3-ynyl, but-2-ynyl,pent-4-ynyl, and hex-5-ynyl. Examples of a C₃-C₈alkynyl group include,but are not limited to, prop-2-ynyl, but-3-ynyl, but-2-ynyl,pent-4-ynyl, hex-5-ynyl, hept-3-ynyl, 2-methylhex-3-ynyl, oct-4-ynyl,and 2-methylhept-3-ynyl. An alkynyl group can be unsubstituted orsubstituted with one or more groups, including: halogen, —NH₂,(C₁-C₆alkyl)N—, (C₁-C₆alkyl)(C₁-C₆alkyl)N—,—N(C₁-C₃alkyl)C(O)(C₁-C₆alkyl), —NHC(O)(C₁-C₆alkyl), —NHC(O)H, —C(O)NH₂,—C(O)NH(C₁-C₆alkyl), —C(O)N(C₁-C₆alkyl)(C₁-C₆alkyl), —CN, hydroxyl,C₁-C₆alkoxy, C₁-C₆alkyl, —C(O)OH, —C(O)O(C₁-C₆alkyl), —C(O)(C₁-C₆alkyl),C₆-C₁₄aryl, C₁-C₉heteroaryl, and C₃-C₈cycloalkyl.

“Alkoxy-” refers to the group R—O— where R is an alkyl group, as definedabove. Exemplary C₁-C₆alkoxy- groups include but are not limited tomethoxy, ethoxy, n-propoxy, 1-propoxy, n-butoxy and t-butoxy. An alkoxygroup can be unsubstituted or substituted with one or more of thefollowing groups: halogen, hydroxyl, C₁-C₆alkoxy-, H₂N—,(C₁-C₆alkyl)amino-, di(C₁-C₆alkyl)amino-,(C₁-C₆alkyl)C(O)N(C₁-C₃alkyl)-, (C₁-C₆alkyl)carboxyamido-, HC(O)NH—,H₂NC(O)—, (C₁-C₆alkyl)NHC(O)—, di(C₁-C₆alkyl)NC(O)—, NC—, C₁-C₆alkoxy-,HO₂C—, (C₁-C₆alkoxy)carbonyl-, (C₁-C₆alkyl)C(O)—, C₆-C₁₄aryl-,C₁-C₉heteroaryl-, C₃-C₈cycloalkyl-, C₁-C₆haloalkyl-, amino(C₁-C₆alkyl)-,(C₁-C₆alkyl)carboxyl-, C₁-C₆-carboxyamidoalkyl-, or O₂N—.

“(Alkoxy)carbonyl-” refers to the group alkyl-O—C(O)—. Exemplary(C₁-C₆alkoxy)carbonyl-groups include but are not limited to methoxy,ethoxy, n-propoxy, 1-propoxy, n-butoxy and t-butoxy. An (alkoxy)carbonylgroup can be unsubstituted or substituted with one or more of thefollowing groups: halogen, hydroxyl, H₂N—, (C₁-C₆alkyl)amino-,di(C₁-C₆alkyl)amino-, (C₁-C₆alkyl)C(O)N(C₁-C₃alkyl)-,(C₁-C₆alkyl)carboxyamido-, HC(O)NH—, H₂NC(O)—, (C₁-C₆alkyl)NHC(O)—,di(C₁-C₆alkyl)NC(O)—, NC—, C₁-C₆alkoxy-, HO₂C—, (C₁-C₆alkoxy)carbonyl-,(C₁-C₆alkyl)C(O)—, C₆-C₁₄aryl-, C₁-C₉heteroaryl-, C₃-C₈cycloalkyl-,C₁-C₆haloalkyl-, amino(C₁-C₆alkyl)-, (C₁-C₆alkyl)carboxyl-,C₁-C₆-carboxyamidoalkyl-, or O₂N—.

“(Alkyl)amido-” refers to a —C(O)NH— group in which the nitrogen atom ofsaid group is attached to a C₁-C₆alkyl group, as defined above.Representative examples of a (C₁-C₆alkyl)amido-group include, but arenot limited to, —C(O)NHCH₃, —C(O)NHCH₂CH₃, —C(O)NHCH₂CH₂CH₃,—C(O)NHCH₂CH₂CH₂CH₃, —C(O)NHCH₂CH₂CH₂CH₂CH₃, —C(O)NHCH(CH₃)₂,—C(O)NHCH₂CH(CH₃)₂, —C(O)NHCH(CH₃)CH₂CH₃, —C(O)NH—C(CH₃)₃ and—C(O)NHCH₂C(CH₃)₃.

“(Alkyl)amino-” refers to an —NH group, the nitrogen atom of said groupbeing attached to a alkyl group, as defined above. Representativeexamples of an (C₁-C₆alkyl)amino- group include, but are not limited toCH₃NH—, CH₃CH₂NH—, CH₃CH₂CH₂NH—, CH₃CH₂CH₂CH₂NH—, (CH₃)₂CHNH—,(CH₃)₂CHCH₂NH—, CH₃CH₂CH(CH₃)NH— and (CH₃)₃CNH—. An (alkyl)amino groupcan be unsubstituted or substituted with one or more of the followinggroups: halogen, H₂N—, (C₁-C₆alkyl)amino-, di(C₁-C₆alkyl)amino-,(C₁-C₆alkyl)C(O)N(C₁-C₃alkyl)-, (C₁-C₆alkyl)carboxyamido-, HC(O)NH—,H₂NC(O)—, (C₁-C₆alkyl)NHC(O)—, di(C₁-C₆alkyl)NC(O)—, NC—, hydroxyl,C₁-C₆alkoxy-, C₁-C₆alkyl-, HO₂C—, (C₁-C₆alkoxy)carbonyl-,(C₁-C₆alkyl)C(O)—, C₆-C₁₄aryl-, C₁-C₉heteroaryl-, C₃-C₈cycloalkyl-,C₁-C₆haloalkyl-, amino(C₁-C₆alkyl)-, (C₁-C₆alkyl)carboxyl-,C₁-C₆-carboxyamidoalkyl-, or O₂N—.

“Aminoalkyl-” refers to an alkyl group, as defined above, wherein one ormore of the alkyl group's hydrogen atoms has been replaced with —NH₂;one or both H of the NH₂ may be replaced by a substituent.

“Alkylcarboxyl-” refers to an alkyl group, defined above that isattached to the parent structure through the oxygen atom of acarboxyl(C(O)—O—) functionality. Examples of (C₁-C₆alkyl)carboxyl-include acetoxy, propionoxy, propylcarboxyl, and isopentylcarboxyl.

“(Alkyl)carboxyamido-” refers to a —NHC(O)— group in which the carbonylcarbon atom of said group is attached to a C₁-C₆alkyl group, as definedabove. Representative examples of a (C₁-C₆alkyl)carboxyamido- groupinclude, but are not limited to, —NHC(O)CH₃, —NHC(O)CH₂CH₃,—NHC(O)CH₂CH₂CH₃, —NHC(O)CH₂CH₂CH₂CH₃, —NHC(O)CH₂CH₂CH₂CH₂CH₃,—NHC(O)CH(CH₃)₂, —NHC(O)CH₂CH(CH₃)₂, —NHC(O)CH(CH₃)CH₂CH₃,—NHC(O)—C(CH₃)₃ and —NHC(O)CH₂C(CH₃)₃.

“Alkylene”, “alkenylene”, and “alkynylene” refers to alkyl, alkenyl andalkynyl groups, as defined above, having two points of attachment withina chemical structure. Examples of C₁-C₆alkylene include ethylene,propylene, and dimethylpropylene. Likewise, examples of C₂-C₆alkenyleneinclude ethenylene and propenylene. Examples of C₂-C₆alkynylene includeethynylene and propynylene.

Aryl refers to an aromatic hydrocarbon group. Examples of a C₆-C₁₄arylgroup include, but are not limited to, phenyl, α-naphthyl, β-naphthyl,biphenyl, anthryl, tetrahydronaphthyl, fluorenyl, indanyl, biphenylenyl,and acenanaphthyl. Examples of a C₆-C₁₀aryl group include, but are notlimited to, phenyl, α-naphthyl, β-naphthyl, biphenyl, andtetrahydronaphthyl. An aryl group can be unsubstituted or substitutedwith one or more groups, including: C₁-C₆alkyl, halo, haloalkyl-,hydroxyl, hydroxyl(C₁-C₆alkyl)-, —NH₂, aminoalkyl-, dialkylamino-,—COOH, —C(O)O—(C₁-C₆alkyl), —OC(O)(C₁-C₆alkyl), N-alkylamido-, —C(O)NH₂,(C₁-C₆alkyl)amido-, or —NO₂.

“(Aryl)alkyl” refers to an alkyl group, as defined above, wherein one ormore of the alkyl group's hydrogen atoms has been replaced with an arylgroup as defined above. (C₆-C₁₄Aryl)alkyl-moieties include benzyl,benzhydryl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl,2-phenylpropyl, 1-naphthylmethyl, 2-naphthylmethyl and the like. An(aryl)alkyl group can be unsubstituted or substituted with one or moreof the following groups: halogen, H₂N—, hydroxyl, (C₁-C₆alkyl)amino-,di(C₁-C₆alkyl)amino-, (C₁-C₆alkyl)C(O)N(C₁-C₃alkyl)-,(C₁-C₆alkyl)carboxyamido-, HC(O)NH—, H₂NC(O)—, (C₁-C₆alkyl)NHC(O)—,di(C₁-C₆alkyl)NC(O)—, NC—, hydroxyl, C₁-C₆alkoxy-, C₁-C₆alkyl-, HO₂C—,(C₁-C₆alkoxy)carbonyl-, (C₁-C₆alkyl)C(O)—, C₆-C₁₄aryl-,C₁-C₉heteroaryl-, C₃-C₈cycloalkyl-, C₁-C₆haloalkyl-, amino(C₁-C₆alkyl)-,(C₁-C₆alkyl)carboxyl-, C₁-C₆-carboxyamidoalkyl-, or O₂N—.

“(Aryl)amino” refers to a radical of formula (aryl)-NH—, wherein aryl isas defined above. “(Aryl)oxy” refers to the group Ar—O— where Ar is anaryl group, as defined above.

“Cycloalkyl” refers to a non-aromatic, saturated, monocyclic, bicyclicor polycyclic hydrocarbon ring system. Representative examples of aC₃-C₁₂cycloalkyl include, but are not limited to, cyclopropyl,cyclopentyl, cycloheptyl, cyclooctyl, decahydronaphthalen-1-yl,octahydro-1H-inden-2-yl, decahydro-1H-benzo[7]annulen-2-yl, anddodecahydros-indacen-4-yl. Representative examples of a C₃-C₁₀cycloalkylinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl, decahydronaphthalen-1-yl, andoctahydro-1H-inden-2-yl. Representative examples of a C₃-C₈cycloalkylinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl, and octahydropentalen-2-yl. Acycloalkyl can be unsubstituted or substituted with one or more groups,including: halogen, —NH₂, (C₁-C₆alkyl)N—, (C₁-C₆alkyl)(C₁-C₆alkyl)N—,—N(C₁-C₃alkyl)C(O)(C₁-C₆alkyl), —NHC(O)(C₁-C₆alkyl), —NHC(O)H, —C(O)NH₂,—C(O)NH(C₁-C₆alkyl), —C(O)N(C₁-C₆alkyl)(C₁-C₆alkyl), —CN, hydroxyl,C₁-C₆alkoxy, C₁-C₆alkyl, —C(O)OH, —C(O)O(C₁-C₆alkyl), —C(O)(C₁-C₆alkyl),C₆-C₁₄aryl, C₁-C₉heteroaryl, C₃-C₈cycloalkyl, C₁-C₆haloalkyl-,C₁-C₆-aminoalkyl-, —OC(O)(C₁-C₆alkyl), C₁-C₆-carboxyamidoalkyl-, and—NO₂. Additionally, each of any two hydrogen atoms on the same carbonatom of the carbocyclic ring can be replaced by an oxygen atom to forman oxo (═O) substituent.

“Cycloalkenyl” refers to a non-aromatic, unsaturated, monocyclic,bicyclic or polycyclic hydrocarbon ring system containing at least onedouble bond connecting two ring carbon atoms. Representative examples ofa C₅-C₈cycloalkenyl include, but are not limited to, cyclopentenyl,cyclohexenyl, 4,4a-octalin-3-yl, and cyclooctenyl. A cycloalkenyl can beunsubstituted or substituted with one or more groups, including:halogen, —NH₂, (C₁-C₆alkyl)N—, (C₁-C₆alkyl)(C₁-C₆alkyl)N—,—N(C₁-C₃alkyl)C(O)(C₁-C₆alkyl), —NHC(O)(C₁-C₆alkyl), —NHC(O)H, —C(O)NH₂,—C(O)NH(C₁-C₆alkyl), —C(O)N(C₁-C₆alkyl)(C₁-C₆alkyl), —CN, hydroxyl,C₁-C₆alkoxy, C₁-C₆alkyl, —C(O)OH, —C(O)O(C₁-C₆alkyl), —C(O)(C₁-C₆alkyl),C₆-C₁₄aryl, C₁-C₉heteroaryl, and C₃-C₈cycloalkyl. Additionally, each ofany two hydrogen atoms on the same carbon atom of the carbocyclic ringcan be replaced by an oxygen atom to form an oxo (═O) substituent.

“Di(alkyl)amino-” refers to a nitrogen atom attached to two alkylgroups, as defined above. Each alkyl group can be independentlyselected. Representative examples of an di(C₁-C₆alkyl)amino- groupinclude, but are not limited to, —N(CH₃)₂, —N(CH₂CH₃)(CH₃), —N(CH₂CH₃)₂,—N(CH₂CH₂CH₃)₂, —N(CH₂CH₂CH₂CH₃)₂, —N(CH(CH₃)₂)₂, —N(CH(CH₃)₂)(CH₃),—N(CH₂CH(CH₃)₂)₂, —NH(CH(CH₃)CH₂CH₃)₂, —N(C(CH₃)₃)₂, —N(C(CH₃)₃)(CH₃),and —N(CH₃)(CH₂CH₃). The two alkyl groups on the nitrogen atom, whentaken together with the nitrogen to which they are attached, can form a3- to 7-membered nitrogen containing heterocycle wherein up to two ofthe carbon atoms of the heterocycle can be replaced with —N(H)—,—N(C₁-C₆alkyl)-, —N(C₃-C₈cycloalkyl)-, —N(C₆-C₁₄aryl)-,—N(C₁-C₉heteroaryl)-, —N(amino(C₁-C₆alkyl))-, —N(C₆-C₁₄arylamino)-, —O—,—S—, —S(O)—, or —S(O)₂—.

“Halo” or “halogen” refers to —F, —Cl, —Br and —I.

“C₁-C₆Haloalkyl-” refers to a C₁-C₆alkyl group, as defined above,wherein one or more of the C₁-C₆alkyl group's hydrogen atoms has beenreplaced with —F, —Cl, —Br, or —I. Each substitution can beindependently selected from —F, —Cl, —Br, or —I. Representative examplesof an C₁-C₆haloalkyl-group include, but are not limited to, —CH₂F,—CCl₃, —CF₃, CH₂CF₃, —CH₂Cl, —CH₂CH₂Br, —CH₂CH₂₁, —CH₂CH₂CH₂F,—CH₂CH₂CH₂Cl, —CH₂CH₂CH₂CH₂Br, —CH₂CH₂ CH₂CH₂I, —CH₂CH₂CH₂CH₂CH₂Br,—CH₂CH₂CH₂CH₂CH₂₁, —CH₂CH(Br)CH₃, —CH₂ CH(Cl)CH₂CH₃, —CH(F)CH₂CH₃ and—C(CH₃)₂(CH₂Cl).

“Heteroaryl” refers to a monocyclic, bicyclic, or polycyclic aromaticring system containing at least one ring atom selected from theheteroatoms oxygen, sulfur and nitrogen. Examples of C₁-C₉heteroarylgroups include furan, thiophene, indole, azaindole, oxazole, thiazole,isoxazole, isothiazole, imidazole, N-methylimidazole, pyridine,pyrimidine, pyrazine, pyrrole, N-methylpyrrole, pyrazole,N-methylpyrazole, 1,3,4-oxadiazole, 1,2,4-triazole,1-methyl-1,2,4-triazole, 1H-tetrazole, 1-methyltetrazole, benzoxazole,benzothiazole, benzofuran, benzisoxazole, benzimidazole,N-methylbenzimidazole, azabenzimidazole, indazole, quinazoline,quinoline, and isoquinoline. Bicyclic C₁-C₉heteroaryl groups includethose where a phenyl, pyridine, pyrimidine or pyridazine ring is fusedto a 5 or 6-membered monocyclic heteroaryl ring having one or twonitrogen atoms in the ring, one nitrogen atom together with either oneoxygen or one sulfur atom in the ring, or one O or S ring atom. Examplesof monocyclic C₁-C₄heteroaryl groups include 2H-tetrazole,3H-1,2,4-triazole, furan, thiophene, oxazole, thiazole, isoxazole,isothiazole, imidazole, and pyrrole. A heteroaryl group can beunsubstituted or substituted with one or more groups, including:C₁-C₆alkyl, halo, haloalkyl-, hydroxyl, hydroxyl(C₁-C₆alkyl)-, —NH₂,aminoalkyl-, dialkylamino-, —COOH, —C(O)O—(C₁-C₆alkyl),—OC(O)(C₁-C₆alkyl), N-alkylamido-, —C(O)NH₂, (C₁-C₆alkyl)amido-, or—NO₂.

“(Heteroaryl)alkyl-” refers to an alkyl group, as defined above, whereinone or more of the alkyl group's hydrogen atoms has been replaced with aheteroaryl- group as defined above. Examples of (C₁-C₉heteroaryl)alkyl-moieties include 2-pyridylmethyl, 2-thiophenylethyl, 3-pyridylpropyl,2-quinolinylmethyl, 2-indolylmethyl, and the like. A (heteroaryl)alkylgroup can be unsubstituted or substituted with one or more of thefollowing groups: halogen, H₂N—, hydroxyl, (C₁-C₆alkyl)amino-,di(C₁-C₆alkyl)amino-, (C₁-C₆alkyl)C(O)N(C₁-C₃alkyl)-,(C₁-C₆alkyl)carboxyamido-, HC(O)NH—, H₂NC(O)—, (C₁-C₆alkyl)NHC(O)—,di(C₁-C₆alkyl)NC(O)—, NC—, hydroxyl, C₁-C₆alkoxy-, C₁-C₆alkyl-, HO₂C—,(C₁-C₆alkoxy)carbonyl-, (C₁-C₆alkyl)C(O)—, C₆-C₁₄aryl-,C₁-C₉heteroaryl-, C₃-C₈cycloalkyl-, C₁-C₆haloalkyl-, amino(C₁-C₆alkyl)-,(C₁-C₆alkyl)carboxyl-, C₁-C₆-carboxyamidoalkyl-, or O₂N—.

The term “heteroatom” refers to a sulfur, nitrogen, or oxygen atom.

“Heterocycle” or “heterocyclyl” refers to monocyclic, bicyclic andpolycyclic groups in which at least one ring atom is a heteroatom. Aheterocycle may be saturated or partially saturated. ExemplaryC₁-C₉heterocyclyl- groups include but are not limited to aziridine,oxirane, oxirene, thiirane, pyrroline, pyrrolidine, dihydrofuran,tetrahydrofuran, dihydrothiophene, tetrahydrothiophene, dithiolane,piperidine, 1,2,3,6-tetrahydropyridine-1-yl, tetrahydropyran, pyran,thiane, thiine, piperazine, oxazine, 5,6-dihydro-4H-1,3-oxazin-2-yl,2,5-diazabicyclo[2.2.1]heptane, 2,5-diazabicyclo[2.2.2]octane,3,6-diazabicyclo[3.1.1]heptane, 3,8-diazabicyclo[3.2.1]octane,6-oxa-3,8-diazabicyclo[3.2.1]octane,7-oxa-2,5-diazabicyclo[2.2.2]octane,2,7-dioxa-5-azabicyclo[2.2.2]octane,2-oxa-5-azabicyclo[2.2.1]heptane-5-yl, 2-oxa-5-azabicyclo[2.2.2]octane,3,6-dioxa-8-azabicyclo[3.2.1]octane, 3-oxa-6-azabicyclo[3.1.1]heptane,3-oxa-8-azabicyclo[3.2.1]octan-8-yl,5,7-dioxa-2-azabicyclo[2.2.2]octane,6,8-dioxa-3-azabicyclo[3.2.1]octane, 6-oxa-3-azabicyclo[3.1.1]heptane,8-oxa-3-azabicyclo[3.2.1]octan-3-yl,2-methyl-2,5-diazabicyclo[2.2.1]heptane-5-yl,1,3,3-trimethyl-6-azabicyclo[3.2.1]oct-6-yl,3-hydroxy-8-azabicyclo[3.2.1]octan-8-yl-,7-methyl-3-oxa-7,9-diazabicyclo[3.3.1]nonan-9-yl,9-oxa-3-azabicyclo[3.3.1]nonan-3-yl,3-oxa-9-azabicyclo[3.3.1]nonan-9-yl,3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl,4-methyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl, thiazine, dithiane, anddioxane. The contemplated heterocycle rings or ring systems have aminimum of 3 members. Therefore, for example, C₁heterocyclyl- radicalswould include but are not limited to oxaziranyl, diaziridinyl, anddiazirinyl, C₂heterocyclyl- radicals include but are not limited toaziridinyl, oxiranyl, and diazetidinyl, C₉heterocyclyl- radicals includebut are not limited to azecanyl, tetrahydroquinolinyl, andperhydroisoquinolinyl. A heterocyclyl group can be unsubstituted orsubstituted with one or more groups, including: C₁-C₆alkyl, halo,haloalkyl-, hydroxyl, hydroxyl(C₁-C₆alkyl)-, —NH₂, aminoalkyl-,dialkylamino-, —COOH, —C(O)O—(C₁-C₆alkyl), —OC(O)(C₁-C₆alkyl),N-alkylamido-, —C(O)NH₂, (C₁-C₆alkyl)amido-, or —NO₂.

“Heterocyclyl(alkyl)-” refers to an alkyl group, as defined above,wherein one or more of the alkyl group's hydrogen atoms has beenreplaced with a heterocycle group as defined above.Heterocyclyl(C₁-C₆alkyl)- moieties include 2-pyridylmethyl,1-piperazinylethyl, 4-morpholinylpropyl, 6-piperazinylhexyl, and thelike. A heterocyclyl(alkyl) group can be unsubstituted or substitutedwith one or more of the following groups: halogen, H₂N—,(C₁-C₆alkyl)amino-, di(C₁-C₆alkyl)amino-,(C₁-C₆alkyl)C(O)N(C₁-C₃alkyl)-, (C₁-C₆alkyl)carboxyamido-, HC(O)NH—,H₂NC(O)—, (C₁-C₆alkyl)NHC(O)—, di(C₁-C₆alkyl)NC(O)—, NC—, hydroxyl,C₁-C₆alkoxy-, C₁-C₆alkyl-, HO₂C—, (C₁-C₆alkoxy)carbonyl-,(C₁-C₆alkyl)C(O)—, 4- to 7-membered monocyclic heterocycle, C₆-C₁₄aryl-,C₁-C₉heteroaryl-, or C₃-C₈cycloalkyl-.

“Hydroxylalkyl-” refers to a alkyl group, as defined above, wherein oneor more of the alkyl group's hydrogen atoms has been replaced withhydroxyl groups. Examples of C₁-C₆hydroxylalkyl-moieties include, forexample, —CH₂OH, —CH₂CH₂OH, —CH₂CH₂CH₂OH, —CH₂CH(OH)CH₂OH,—CH₂CH(OH)CH₃, —CH(CH₃)CH₂OH and higher homologs.

“Perfluoroalkyl-” refers to alkyl group, defined above, having two ormore fluorine atoms. Examples of a C₁-C₆ perfluoroalkyl- group includeCF₃, CH₂CF₃, CF₂CF₃ and CH(CF₃)₂.

A “subject” is a mammal, e.g., a human, mouse, rat, guinea pig, dog,cat, horse, cow, pig, or non-human primate, such as a monkey,chimpanzee, baboon or gorilla.

The term “optionally substituted” as used herein means that at least onehydrogen atom of the optionally substituted group has been substitutedwith halogen, —NH₂, —NH(C₁-C₆alkyl), —N(C₁-C₆alkyl)(C₁-C₆alkyl),—N(C₁-C₃alkyl)C(O)(C₁-C₆alkyl), —NHC(O)(C₁-C₆alkyl), —NHC(O)H, —C(O)NH₂,—C(O)NH(C₁-C₆alkyl), —C(O)N(C₁-C₆alkyl)(C₁-C₆alkyl), —CN, hydroxyl,C₁-C₆alkoxy, C₁-C₆alkyl, —C(O)OH, —C(O)O(C₁-C₆alkyl), —C(O)(C₁-C₆alkyl),C₆-C₁₄aryl, C₁-C₉heteroaryl, or C₃-C₈cycloalkyl.

Representative “pharmaceutically acceptable salts” include but are notlimited to, e.g., water-soluble and water-insoluble salts, such as theacetate, aluminum, amsonate (4,4-diaminostilbene-2,2-disulfonate),benzathine (N,N′-dibenzylethylenediamine), benzenesulfonate, benzoate,bicarbonate, bismuth, bisulfate, bitartrate, borate, bromide, butyrate,calcium, calcium edetate, camsylate (camphorsulfonate), carbonate,chloride, choline, citrate, clavulariate, diethanolamine,dihydrochloride, diphosphate, edetate, edisylate (camphorsulfonate),esylate (ethanesulfonate), ethylenediamine, fumarate, gluceptate(glucoheptonate), gluconate, glucuronate, glutamate,hexafluorophosphate, hexylresorcinate,hydrabamine(N,N′-bis(dehydroabietyl)ethylenediamine), hydrobromide,hydrochloride, hydroxynaphthoate, 1-hydroxy-2-naphthoate,3-hydroxy-2-naphthoate, iodide, isothionate (2-hydroxyethanesulfonate),lactate, lactobionate, laurate, lauryl sulfate, lithium, magnesium,malate, maleate, mandelate, meglumine(1-deoxy-1-(methylamino)-D-glucitol), mesylate, methyl bromide,methylnitrate, methylsulfate, mucate, napsylate, nitrate,N-methylglucamine ammonium salt, oleate, oxalate, palmitate, pamoate(4,4′-methylenebis-3-hydroxy-2-naphthoate, or embonate), pantothenate,phosphate, picrate, polygalacturonate, potassium, propionate,p-toluenesulfonate, salicylate, sodium, stearate, subacetate, succinate,sulfate, sulfosaliculate, suramate, tannate, tartrate, teoclate(8-chloro-3,7-dihydro-1,3-dimethyl-1H-purine-2,6-dione), trieth iodide,tromethamine(2-amino-2-(hydroxymethyl)-1,3-propanediol), valerate, andzinc salts.

An “effective amount” when used in connection with a compound of thisinvention is an amount effective for inhibiting mTOR or PI3K in asubject.

Some compounds within the present invention possess one or more chiralcenters, and the present invention includes each separate enantiomer ofsuch compounds as well as mixtures of the enantiomers. Where multiplechiral centers exist in compounds of the present invention, theinvention includes each combination as well as mixtures thereof. Allchiral, diastereomeric, and racemic forms of a structure are intended,unless the specific stereochemistry or isomeric form is specificallyindicated. It is well known in the art how to prepare optically activeforms, such as by resolution of racemic forms or by synthesis fromoptically active starting materials.

The compounds of the present invention exhibit an mTOR inhibitoryactivity and therefore, can be utilized in order to inhibit abnormalcell growth in which mTOR plays a role. Thus, the compounds of thepresent invention are effective in the treatment of disorders with whichabnormal cell growth actions of mTOR are associated, such as restenosis,atherosclerosis, bone disorders, arthritis, diabetic retinopathy,psoriasis, benign prostatic hypertrophy, atherosclerosis, inflammation,angiogenesis, immunological disorders, pancreatitis, kidney disease,cancer, etc. In particular, the compounds of the present inventionpossess excellent cancer cell growth inhibiting effects and areeffective in treating cancers, preferably all types of solid cancers andmalignant lymphomas, and especially, leukemia, skin cancer, bladdercancer, breast cancer, uterus cancer, ovary cancer, prostate cancer,lung cancer, colon cancer, pancreas cancer, renal cancer, gastriccancer, brain tumor, advanced renal cell carcinoma, acute lymphoblasticleukemia, malignant melanoma, soft-tissue or bone sarcoma, etc.

The compounds of the present invention exhibit a PI3 kinase inhibitoryactivity and, therefore, can be utilized in order to inhibit abnormalcell growth in which PI3 kinases play a role. Thus, the compounds of thepresent invention are effective in the treatment of disorders with whichabnormal cell growth actions of PI3 kinases are associated, such asrestenosis, atherosclerosis, bone disorders, arthritis, diabeticretinopathy, psoriasis, benign prostatic hypertrophy, atherosclerosis,inflammation, angiogenesis, immunological disorders, pancreatitis,kidney disease, cancer, etc. In particular, the compounds of the presentinvention possess excellent cancer cell growth inhibiting effects andare effective in treating cancers, preferably all types of solid cancersand malignant lymphomas, and especially, leukemia, skin cancer, bladdercancer, breast cancer, uterus cancer, ovary cancer, prostate cancer,lung cancer, colon cancer, pancreas cancer, renal cancer, gastriccancer, brain tumor, advanced renal cell carcinoma, acute lymphoblasticleukemia, malignant melanoma, soft-tissue or bone sarcoma, etc.

For therapeutic use, the pharmacologically active compounds of Formula Iwill normally be administered as a pharmaceutical composition comprisingas the (or an) essential active ingredient at least one such compound inassociation with a solid or liquid pharmaceutically acceptable carrierand, optionally, with pharmaceutically acceptable adjutants andexcipients employing standard and conventional techniques.

The pharmaceutical compositions of this invention include suitabledosage forms for oral, parenteral (including subcutaneous,intramuscular, intradermal and intravenous) bronchial or nasaladministration. Thus, if a solid carrier is used, the preparation may betableted, placed in a hard gelatin capsule in powder or pellet form, orin the form of a troche or lozenge. The solid carrier may containconventional excipients such as binding agents, fillers, tabletinglubricants, disintegrants, wetting agents and the like. The tablet may,if desired, be film coated by conventional techniques. If a liquidcarrier is employed, the preparation may be in the form of a syrup,emulsion, soft gelatin capsule, sterile vehicle for injection, anaqueous or non-aqueous liquid suspension, or may be a dry product forreconstitution with water or other suitable vehicle before use. Liquidpreparations may contain conventional additives such as suspendingagents, emulsifying agents, wetting agents, non-aqueous vehicle(including edible oils), preservatives, as well as flavoring and/orcoloring agents. For parenteral administration, a vehicle normally willcomprise sterile water, at least in large part, although salinesolutions, glucose solutions and like may be utilized. Injectablesuspensions also may be used, in which case conventional suspendingagents may be employed. Conventional preservatives, buffering agents andthe like also may be added to the parenteral dosage forms. Particularlyuseful is the administration of a compound of Formula I directly inparenteral formulations. The pharmaceutical compositions are prepared byconventional techniques appropriate to the desired preparationcontaining appropriate amounts of the active ingredient, that is, thecompound of Formula I according to the invention. See, for example,Remington: The Science and Practice of Pharmacy, 20th Edition.Baltimore, Md.: Lippincott Williams & Wilkins, 2000.

The dosage of the compounds of Formula I to achieve a therapeutic effectwill depend not only on such factors as the age, weight and sex of thepatient and mode of administration, but also on the degree of potassiumchannel activating activity desired and the potency of the particularcompound being utilized for the particular disorder of diseaseconcerned. It is also contemplated that the treatment and dosage of theparticular compound may be administered in unit dosage form and that oneskilled in the art would adjust the unit dosage form accordingly toreflect the relative level of activity. The decision as to theparticular dosage to be employed (and the number of times to beadministered per day is within the discretion of the physician, and maybe varied by titration of the dosage to the particular circumstances ofthis invention to produce the desired therapeutic effect.

A suitable dose of a compound of Formula I or pharmaceutical compositionthereof for a mammal, including man, suffering from, or likely to sufferfrom any condition as described herein is an amount of active ingredientfrom about 0.01 mg/kg to 10 mg/kg body weight. For parenteraladministration, the dose may be in the range of 0.1 mg/kg to 1 mg/kgbody weight for intravenous administration. For oral administration, thedose may be in the range about 0.1 mg/kg to 5 mg/kg body weight. Theactive ingredient will preferably be administered in equal doses fromone to four times a day. However, usually a small dosage isadministered, and the dosage is gradually increased until the optimaldosage for the host under treatment is determined.

However, it will be understood that the amount of the compound actuallyadministered will be determined by a physician, in the light of therelevant circumstances including the condition to be treated, the choiceof compound of be administered, the chosen route of administration, theage, weight, and response of the individual patient, and the severity ofthe patient's symptoms.

The amount of the compound of the present invention or apharmaceutically acceptable salt thereof that is effective forinhibiting mTOR or PI3K in a subject. In addition, in vitro or in vivoassays can optionally be employed to help identify optimal dosageranges. The precise dose to be employed can also depend on the route ofadministration, the condition, the seriousness of the condition beingtreated, as well as various physical factors related to the individualbeing treated, and can be decided according to the judgment of ahealth-care practitioner. Equivalent dosages may be administered overvarious time periods including, but not limited to, about every 2 hours,about every 6 hours, about every 8 hours, about every 12 hours, aboutevery 24 hours, about every 36 hours, about every 48 hours, about every72 hours, about every week, about every two weeks, about every threeweeks, about every month, and about every two months. The number andfrequency of dosages corresponding to a completed course of therapy willbe determined according to the judgment of a health-care practitioner.The effective dosage amounts described herein refer to total amountsadministered; that is, if more than one compound of the presentinvention or a pharmaceutically acceptable salt thereof is administered,the effective dosage amounts correspond to the total amountadministered.

In one embodiment, the compound of the present invention or apharmaceutically acceptable salt thereof is administered concurrentlywith another therapeutic agent.

In one embodiment, a composition comprising an effective amount of acompound of the present invention or a pharmaceutically acceptable saltthereof and an effective amount of another therapeutic agent within thesame composition can be administered.

Effective amounts of the other therapeutic agents are well known tothose skilled in the art. However, it is well within the skilledartisan's purview to determine the other therapeutic agent's optimaleffective amount range. The compound of the present invention or apharmaceutically acceptable salt thereof and the other therapeutic agentcan act additively or, in one embodiment, synergistically. In oneembodiment, of the invention, where another therapeutic agent isadministered to an animal, the effective amount of the compound of thepresent invention or a pharmaceutically acceptable salt thereof is lessthan its effective amount would be where the other therapeutic agent isnot administered. In this case, without being bound by theory, it isbelieved that the compound of the present invention or apharmaceutically acceptable salt thereof and the other therapeutic agentact synergistically.

Methods useful for making the compounds of Formula I are set forth inthe Examples below and generalized in Schemes 1-3:

Scheme 1:

One of skill in the art will recognize that Schemes 1-3 can be adaptedto produce the other compounds of Formula I and pharmaceuticallyacceptable salts of compounds of Formula I according to the presentinvention.

The following abbreviations are used herein and have the indicateddefinitions: ACN is acetonitrile, AcOH is acetic acid, ATP is adenosinetriphosphate, CHAPS is3-[(3-cholamidopropyl)dimethylammonio]-propanesulfonic acid, DEAD isdiethyl azodicarboxylate, DIAD is diisopropyl azodicarboxylate, DMAP isdimethyl aminopyridine, DMF is N,N-dimethylformamide, DMF-DMA isdimethylformamide dimethyl acetal, DMSO is dimethylsulfoxide. Dowtherm™is a eutectic mixture of biphenyl(C₁₂H₁₀) and diphenyl oxide (C₁₂H₁₀O).Dowtherm™ is a registered trademark of Dow Corning Corporation. DPBS isDulbecco's Phosphate Buffered Saline Formulation, EDTA isethylenediaminetetraacetic acid, ESI stands for Electrospray Ionization,EtOAc is ethyl acetate, EtOH is ethanol, HEPES is4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid, GMF is Glass,Hunig's Base is diisopropylethylamine, HPLC is high pressure liquidchromatography, LPS is lipopolysaccharide, MeCN is acetonitrile, MeOH ismethanol, MS is mass spectrometry, NEt₃ is triethylamine, NMR is nuclearmagnetic resonance, PBS is phosphate-buffered saline (pH 7.4), RPMI 1640is a buffer (Sigma-Aldrich Corp., St. Louis, Mo., USA), SDS is dodecylsulfate (sodium salt), SRB is Sulforhodamine B, TBSCl istert-butyldimethylsilyl chloride, TCA is tricholoroacetic acid, TFA istrifluoroacetic acid, THF is tetrahydrofuran, TLC is thin-layerchromatography, and TRIS is tris(hydroxymethyl)aminomethane.

Methods

The following methods outline the synthesis of the compounds of FormulaI. The following examples are presented to illustrate certainembodiments of the present invention, but should not be construed aslimiting the scope of this invention.

Example 1 Preparation of1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-pyridin-4-ylureaStep 1: Preparation of 2-chloro-4,6-di-morpholin-4-yl-[1,3,5]triazine

To a stirred solution of cyanuric chloride (18.4 g, 10 mmol) in acetone(100 ml) and crushed ice (500 g), a mixture of triethylamine (30.0 g,excess) and morpholine (17.4 g, 20 mmol) was added at −10° C. After theaddition, reaction mixture was stirred at room temperature and for 1hour and diluted with 50 ml water. Separated white solid was filteredand washed with water. The white solid was dried and filtered. The crudeproduct was found to be pure and taken to next step withoutpurification. Yield: 25 g, 87%; (M+H) 286.7.

Step 2: Preparation of4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline

A mixture of 2-chloro-4,6-di-morpholin-4-yl-[1,3,5]triazine (1.4 g, 4.9mmoles), a catalytic amount of tetrakis(triphenylphosphine)palladium(0)(70 mg, 0.061 mmoles), sodium carbonate solution 2 M (3 mL),4-aminophenylboronic acid pinacol ester (1.6 g, 7.3 mmoles) and DME (100mL) was refluxed for 24 hours. The solvent was evaporated, and theresidue was dissolved in methylene chloride and filtered throughCelite™. The filtrate was washed with water (200 mL) and the organiclayer was dried with magnesium sulfate. This was filtered and thesolvent was evaporated. The residue was purified by Silica gel columnchromatography and eluted with Ethyl acetate/hexanes (1:1) to give 1.40g, (83% yield) of 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline asan amorphous solid. (M+H) 343.

Step 3: Preparation of1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-pyridin-4-ylurea

To a mixture of 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline (0.20g 0.40 mmoles) in methylene chloride (80 mL) at 0° C. was addedtriphosgene (0.25 mg, 0.84 mmoles) and triethylamine (3 mL). The mixturewas stirred for 20 minutes at 0° C. and 4-amino pyridine (0.10 g 0.83mmoles) was added to the reaction mixture and stirred for another 2hours at room temperature. The solvent was evaporated and the residuewas submitted to the HPLC using acetonitrile/TFA as mobile phase to give98.2 mg (36% yield) of1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-pyridin-4-ylurea.(M+H)=463.3.

Procedure A for Preparation of Ureas Using Aryl Isocyanates

To a stirred mixture of4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline (140 mg, 0.40 mmoles)and a catalytic amount of dimethylaminopyridine (DMAP) in methylenechloride 100 (mL), was added a small excess of aryl isocyanate (0.61mmoles). The mixture was stirred at room temperature for 48 hours. Thereaction mixture was concentrated to half of its original volume and theseparated precipitate was collected by filtration and washed withmethanol (15 ml) and then with diethyl ether. In some cases the crudeproduct obtained was purified by Silica gel column chromatography byeluting it with appropriate solvents, depending upon the polarity of theproducts.

The following compounds were prepared according to Procedure A:

Example 2 Preparation of1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-pyridin-3-ylurea

Starting from 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline (0.08 g0.23 mmoles) and 3-pyridyl isocyanate (30 mg, 0.25 mmoles) the titlecompound was isolated as a white solid. The product was purified bySilica gel column chromatography by eluting it with 10% MeOH: ethylacetate. Yield; 60 mg (56%); (M+H)=463.5.

Example 3 Preparation of1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-phenylurea

Starting from 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline (140mg, 0.40 mmoles) and phenyl isocyanate (72 mg, 0.61 mmoles), the titlecompound was isolated as a white solid. The product was purified bySilica gel column chromatography by eluting it with ethyl acetate.Yield: 0.128 g (68%) (M+H)=462.3.

Example 4 Preparation of1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-thiophen-2-ylurea

Starting from 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline (60 mg,0.17 mmoles) and 2-thienyl isocyanate (18 mg, 0.14 mmoles), the titlecompound was isolated as a grey solid after Silica gel columnchromatography by eluting with 5% ethyl acetate: methanol. Yield: 12 mg(14%); (M+H)=470.

Example 5 Preparation of1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-(4-methylphenyl)urea

Starting from 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline (0.140g 0.40 mmoles) and 4-methylphenyl isocyanate (74 mg, 0.56 mmoles), thetitle compound was isolated as a white solid. Yield; 65 mg (33%)(M+H)=476.4.

Example 6 Preparation of1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-(4-fluorophenyl)urea

Starting from 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline (0.140g 0.40 mmoles) and 4-fluorophenyl isocyanate (83 mg, 0.61 mmole), 65 mg(33% yield) of the title product was isolated as white solid.(M+H)=480.3.

Example 7 Preparation of1-(2,4-dimethoxyphenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-urea

Starting from 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline (0.140g 0.40 mmoles) and 2,4-dimethoxyphenyl isocyanate (131 mg, 0.73 mmoles),the title compound was isolated as a white solid. Yield; 76 mg (36%);(M+H)=522.4.

Example 8 Preparation of1-(4-chlorophenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-urea

Starting from 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline (0.140g 0.40 mmoles) and 4-chlorophenyl isocyanate (94 mg, 0.61 mmoles), thetitle compound was isolated as a white solid. Yield; 60 mg (30%);(M+H)=496.3.

Example 9 Preparation1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-(4-methoxyphenyl)urea

Starting from 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline (0.140g 0.40 mmoles) and 4-methoxyphenyl isocyanate (91 mg, 0.63 mmoles) thetitle compound was isolated as a white solid. Yield; 48 mg (24%);(M+H)=492.3.

Example 10 Preparation of(4-chlorophenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea

Starting from 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline (0.140g 0.40 mmoles) and 4-chlorophenyl isocyanate (94 mg, 0.61 mmoles) thetitle compound was isolated as a white solid. Yield; 60 mg (30%);(M+H)=496.3

Example 11 Preparation of(2,4-difluorophenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea

Starting from 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline (0.105g 0.30 mmoles) and 2,4-difluorophenyl isocyanate (71 mg, 0.45 mmoles)the title compound was isolated as a white solid. Yield; 40 mg (27%);(M+H)=498.6

Example 12 Preparation of1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-ethylurea

Starting from 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline (0.130g 0.38 mmoles) and ethyl isocyanate (260 mg, 10 fold excess) the titlecompound was isolated as a white solid. Yield; 38 mg (25%); (M+H)=414.4

Example 13 Preparation of tert-butyl3-{[4-(4-{[(4-fluorophenyl)carbamoyl]-amino}phenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]amino}azetidine-1-carboxylateStep 1: Preparation of 2,4-dichloro-6-morpholin-4-yl-[1,3,5]triazine

To a stirred solution of cyanuric chloride (18.4 g, 10 mmol) in acetone(100 ml) and crushed ice (500 g), a mixture of triethylamine (30.0 g,excess) and morpholine (8.7 g, 10 mmol) was added at −10° C. After theaddition, reaction mixture was stirred at room temperature and for 1hour and diluted with 50 ml water. Separated white solid was filteredand washed with water. The white solid was dried and filtered. The crudeproduct was found to be pure and taken to next step with outpurification. Yield: 18 g, 76%; (M+H) 236.4.

Step 2: Preparation of tert-butyl3-(4-chloro-6-morpholine-1,3,5-triazin-2-2-ylamino)azetidine-1-carboxylate

To a stirred solution of 2,4-dichloro-6-morpholin-4-yl-[1,3,5]triazine(2.35 g, 10 mmol) in acetone (50 ml) and crushed ice, a mixture oftriethylamine and 1-boc-3-(amino)azetidine (1.72 g) was added slowly.The reaction mixture was stirred at room temperature for 6 hours and theseparated solid was filtered. The product was dried and taken to nextstep with out purification. Yield: 3.0 g (81%); (M+H) 373.

Step 3: Preparation oftert-butyl-3-4-(4-(4-aminophenyl)-6-morpholine-1,3,5-triazin-2-ylamino)azetidine-1-carboxylate

A mixture of tert-butyl3-(4-chloro-6-morpholine-1,3,5-triazin-2-2-ylamino)azetidine-1-carboxylate(1.1 g, 3.0 mmoles), tetrakis(triphenylphosphine)palladium (0) incatalytic amount (70 mg, 0061 mmoles), sodium carbonate solution 2 M (3mL), 4-aminophenylboronic acid pinacol ester (0.97 g, 4.5 mmoles), DME(100 mL) was refluxed for 24 hours. The solvent was evaporated and theresidue was dissolved in methylene chloride and filtered though Celite™.The organic layer was washed with water (200 mL) and dried overmagnesium sulfate. It was filtered and the solvent was evaporated. Theresidue was chromatographed on silica gel column using Ethylacetate/hexanes (1:1) as an eluent, to give 0.86 g, (68% yield) oftert-butyl-3-4-(4-(4-aminophenyl)-6-morpholine-1,3,5-triazin-2-ylamino)azetidine-1-carboxylate.(M+H) 428.

Step 4: Preparation of tert-butyl3-{[4-(4-{[(4-fluorophenyl)carbamoyl]amino}phenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]amino}azetidine-1-carboxylate

A mixture of tert-butyl3-{[4-(4-aminophenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]amino}azetidine-1-carboxylate(100 mg, 0.23 mmol), 4-fluorophenylisocyanate (63 mg, 0.46 mmol) andDMAP (5 mg) was stirred at room temperature for a period of 24 h. At theend, reaction mixture was concentrated and purified by Gilson HPLC,using ACN/water and TFA. White solid; Yield 40 mg (30%); (M+H) 565.6.

Example 14 Preparation of tert-butyl3-[(4-morpholin-4-yl-6-{4-[(phenylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl)amino]azetidine-1-carboxylate

The titled compound was prepared by starting from tert-butyl3-{[4-(4-aminophenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]amino}azetidine-1-carboxylate(140 mg, 0.32 mmol) phenylisocyanate (58 mg, 0.49 mmol) and DMAP (5 mg)was stirred at room temperature for a period of 24 h. At the end,reaction mixture was concentrated and purified by Gilson HPLC, usingACN/water and TFA. White solid; Yield 40 mg (31%); (M+H) 547.6

Example 15 Preparation of tert-butyl3-[(4-morpholin-4-yl-6-{4-[(pyridine-3-ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl)amino]azetidine-1-carboxylate

The titled compound was prepared by starting from tert-butyl3-{[4-(4-aminophenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]amino}azetidine-1-carboxylate(140 mg, 0.32 mmol) 3-pyridylisocyanate (70 mg, 0.58 mmol) and DMAP (5mg) was stirred at room temperature for a period of 24 h. At the end,reaction mixture was concentrated and purified by Gilson HPLC, usingACN/water and TFA. White solid; Yield 40 mg (23%); (M+H) 548.7.

Example 16 Preparation of tert-butyl3-{[4-(4-{[(4-methylphenyl)carbamoyl]amino}phenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]amino}azetidine-1-carboxylate

The titled compound was prepared by starting from tert-butyl3-{[4-(4-aminophenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]amino}azetidine-1-carboxylate(130 mg, 0.27 mmol) 4-tolyl isocyanate (40 mg, 0.30 mmol) and DMAP (5mg) was stirred at room temperature for a period of 24 h. At the end,reaction mixture was concentrated and purified by Gilson HPLC, usingACN/water and TFA. White solid; Yield 85 mg (47%); (M+H) 561.6.

Example 17 Preparation of1-{4-[4-(azetidin-3-ylamino)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-phenylurea

To a stirred solution of tert-butyl3-[(4-morpholin-4-yl-6-{4-[(phenylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl)amino]azetidine-1-carboxylate

30 mg (0.055 mmoles) in DCM, (20 ml) TFA (1.5 ml) was added at roomtemperature and stirred for 24 h. At the end, reaction mixture wasconcentrated and purified by Gilson HPLC, using ACN/water and TFA.Yield: 20 (83%); (M+H) 447.

Example 18 Preparation of1-{4-[4-(azetidin-3-ylamino)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylureaTo a stirred solution of tert-butyl3-[(4-morpholin-4-yl-6-{4-[(pyridin-3-ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl)amino]azetidine-1-carboxylate

30 mg (0.055 mmoles) in DCM, (20 ml) TFA (1.5 ml) was added at roomtemperature and stirred for 24 h. At the end, reaction mixture wasconcentrated and purified by Gilson HPLC, using ACN/water and TFA.Yield: 21 (83%); (M+H) 448.5.

Example 19 Preparation of1-{4-[4-(azetidin-3-ylamino)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-(4-fluorophenyl)ureaTo a stirred solution of tert-butyl3-[(4-morpholin-4-yl-6-{4-[(4-fluoro-phenylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl)amino]azetidine-1-carboxylate

30 mg (0.053 mmoles) in DCM, (20 ml) TFA (1.5 ml) was added at roomtemperature and stirred for 24 h. At the end, reaction mixture wasconcentrated and purified by Gilson HPLC, using ACN/water and TFA.Yield: 20 (83%); (M+H) 465.5.

Example 20 Preparation of1-{4-[4-(azetidin-3-ylamino)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-(4-methylphenyl)ureaTo a stirred solution of tert-butyl3-[(4-morpholin-4-yl-6-{4-[(4-methyl-phenylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl)amino]azetidine-1-carboxylate

130 mg (0.23 mmoles) in DCM, (20 ml) TFA (1.5 ml) was added at roomtemperature and stirred for 24 h. At the end, reaction mixture wasconcentrated and purified by Gilson HPLC, using ACN/water and TFA.Yield: 40 (37%); (M+H) 461.5.

Example 21 Preparation of tert-butyl3-[(4-morpholin-4-yl-6-{4-[(pyridine-4-ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl)amino]azetidine-1-carboxylate

To a stirred solution of tert-butyl3-{[4-(4-aminophenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]amino}azetidine-1-carboxylate(200 mg, 0.47 mmol) in DCM (100 ml) at 0° C., triphosgene (300 mg) andtriethylamine (3 ml) was added slowly. The reaction mixture was stirredfor 15 minutes and 4-aminopyridine (200 mg. 2.1 mmol) was added. Thereaction mixture was stirred at room temperature for 24 hours andconcentrated. It was quenched with cold water and the separated solidwas filtered and washed with water. It was dried and purified by GilsonHPLC. Yield 100 mg (40%); (M+H) 548.6

Example 22 Preparation of1-{4-[4-(azetidin-3-ylamino)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylureaTo a stirred solution of tert-butyl3-[(4-morpholin-4-yl-6-{4-[(pyridine-4-ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl)amino]azetidine-1-carboxylate

40 mg (0.073 mmoles) in DCM, (20 ml) TFA (1.5 ml) was added at roomtemperature and stirred for 24 h. At the end, reaction mixture wasconcentrated and purified by Gilson HPLC, using ACN/water and TFA.Yield: 26 (81%); (M+H) 448.5.

Example 23 Preparation of1-{4-[4-morpholin-4-yl-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-phenylureaStep 1: Preparation of3-(4-chloro-6-morpholin-4-yl-1,3,5-triazin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane

To a stirred acetone/crushed ice suspension of2,4-dichloro-6-morpholin-4-yl-[1,3,5]triazine (1.5 g, 6.5 mmol),8-oxa-3-azabicyclo[3.2.1]octane (980 mg, 6.5 mmol) and triethylamine (3ml) was added and stirred at room temperature for 6 h. At the end, theseparated solid was filtered and washed with water. The crude productwas found to be pure enough for further transformations. Yield: 2.0 g(99%); mp. 118; (M+H) 313.1.

Step 2: Preparation of4-[4-morpholin-4-yl-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]aniline

A mixture of3-(4-chloro-6-morpholin-4-yl-1,3,5-triazin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane(2.0 g, 6.4 mmol), tetrakis(triphenylphosphine)palladium (0) incatalytic amount (100 mg), sodium carbonate solution 2 M (5 mL),4-aminophenylboronic acid pinacol ester (1.5 g, 6.43 mmoles), DME (200mL) was refluxed for 24 hours. The solvent was evaporated and theresidue was dissolved in methylene chloride and filtered though Celite™.The organic layer was washed with water (200 mL) and dried overmagnesium sulfate. It was filtered and the solvent was evaporated. Theresidue was chromatographed on silica gel column using Ethylacetate/hexanes (1:1) as an eluent, to give 1.4 g, (59% yield) of thetitled product. mp. 154; (M+H) 369.4.

Step 3: Preparation of1-{4-[4-morpholin-4-yl-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-phenylurea

The titled compound was prepared by starting from4-[4-morpholin-4-yl-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]aniline(120 mg, 0.32 mmol) phenylisocyanate (80 mg, 0.67 mmol) and DMAP (5 mg)was stirred at room temperature for a period of 24 h. At the end,reaction mixture was concentrated and purified by Gilson HPLC, usingACN/water and TFA. White solid; mp: 242; Yield 35 mg (28%); (M+H) 488.56

Example 24 Preparation of1-(4-fluorophenyl)-3-{4-[4-morpholin-4-yl-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}urea

The titled compound was prepared by starting from4-[4-morpholin-4-yl-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]aniline(100 mg, 0.27 mmol)-4-fluoro phenylisocyanate (50 mg, 0.36 mmol) andDMAP (5 mg) was stirred at room temperature for a period of 24 h. At theend, reaction mixture was concentrated and purified by Gilson HPLC,using ACN/water and TFA. White solid; mp: 248; Yield 86 mg (86%); (M+H)506.4.

Example 25 Preparation of1-(4-methylphenyl)-3-{4-[4-morpholin-4-yl-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}urea

The titled compound was prepared by starting from4-[4-morpholin-4-yl-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]aniline(100 mg, 0.27 mmol)-4-tolylisocyanate (60 mg, 0.45 mmol) and DMAP (5 mg)was stirred at room temperature for a period of 24 h. At the end,reaction mixture was concentrated and purified by Gilson HPLC, usingACN/water and TFA. White solid; mp: 228; Yield 80 mg (80%); (M+H) 502.4

Following the procedure as outlined in example 25, compounds describedin examples 26 to 32 were prepared.

Example 261-[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-yl-1,3,5-triazin-2-yl)phenyl]-3-methylurea(M+H) 452.53 Example 272-hydroxyethyl[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-yl-1,3,5-triazin-2-yl)phenyl]carbamate(M+H) 483.54 Example 281-[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(4-methylpiperazin-1-yl)phenyl]urea(M+H) 612.8 Example 291-[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-yl-1,3,5-triazin-2-yl)phenyl]-3-ethylurea(M+H) 466.56 Example 301-cyclopropyl-3-[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-yl-1,3,5-triazin-2-yl)phenyl]urea(M+H) 478.55 Example 311-[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-yl-1,3,5-triazin-2-yl)phenyl]-3-pyridin-4-ylurea(M+H) 515 Example 321-[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(hydroxymethyl)phenyl]urea(M+H) 544.6 Example 33 Preparation of4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]anilineStep 1: Synthesis of 4-(4,6-dichloro-1,3,5-triazin-2-yl)morpholine

To a solution of cyanuric chloride (2.5 g, 13.5 mmol) in CH₂Cl₂ (150 mL)was added dropwise morpholine (1.14 g, 13.5 mmol) at −78° C., followedby addition of Et₃N (3.0 mL, 21.5 mmol). The resulting reaction mixturewas stirred at −78° C. for 20 min, and then diluted with CH₂Cl₂. Theorganic phase was washed with water and brine, and dried over MgSO₄. Thesolvent was removed in vacuum to give the title compound as whitecrystalline solid (3.027 g, 95% yield). MS (ESI) m/z 235.1.

Step 2: Synthesis of8-(4-chloro-6-morpholino-1,3,5-triazin-2-yl)-3-oxa-8-azabicyclo[3,2,1]octane

To a solution of 4-(4,6-dichloro-1,3,5-triazin-2-yl)morpholine (2.34 g,10 mmol) in CH₂Cl₂ (100 mL) were added 3-oxa-8-azabicyclo[3,2,1]octanehydrochloride (1.645 g, 11 mmol) and Et₃N (4.2 mL, 30 mmol). The mixturewas stirred at room temperature over night. The reaction mixture waswashed with water and brine, and dried over MgSO₄. The solvent wasremoved in vacuum to give the title compound as white solid (3.0 g, 96%yield). MS (ESI) m/z 312.1.

Step 3: Synthesis of4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]aniline

To a 10 mL vial were added8-(4-chloro-6-morpholino-1,3,5-triazin-2-yl)-3-oxa-8-azabicyclo[3,2,1]octane(311 mg, 1.0 mmol), 4-aminophenylboronic acid pinacol ester (328 mg, 1.5mmol), Pd(PPh₃)₄ (58 mg, 5 mol %), 1,2-dimethoxyethane (DME, 2.5 mL) and2M Na₂CO₃ aqueous solution (1.5 mL). The resulting mixture was heated at130° C. for 30 min in microwave oven. The reaction mixture was cooled toroom temperature. The aqueous phase was extracted with EtOAc, and thecombined organic phases were dried over (MgSO₄). The solvent was removedunder reduced pressure and the residue was subjected to HPLC separationto give the title compound as off-white solid (280 mg, 76% yield). MS(ESI) m/z 369.2.

Example 34 Preparation of1-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea

To a solution of4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]aniline(22 mg, 0.06 mmol) in CHCl3 (1 mL) were added Et₃N (25 mL, 0.18 mmol)and triphosgene (18 mg, 0.06 mmol). The mixture was stirred at roomtemperature for 15 min and 4-aminopyridine (17 mg, 0.18 mmol) was added.The mixture was stirred at room temperature overnight. The solvent wasremoved, and the residue was subjected to HPLC separation to give thetitle compound as off-white solid (1TFA salt, 8.8 mg, 24% yield). MS(ESI) m/z 489.2.

Example 35 Preparation of4-[({4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide

Following the procedure described in example 34, reaction of4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]aniline(22 mg, 0.06 mmol) (22 mg, 0.06 mmol, triphosgene (18 mg, 0.06 mmol) and4-aminobenzamide (25 mg, 0.18 mmol) gave the title compound as off-whitesolid (10.6 mg, 33% yield). MS (ESI) m/z 531.2.

Example 36 Preparation of1-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea

Following the procedure described in example 34, reaction of4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]aniline(22 mg, 0.06 mmol) (22 mg, 0.06 mmol, triphosgene (18 mg, 0.06 mmol) and3-aminopyridine (17 mg, 0.18 mmol) gave the title compound as off-whitesolid (1TFA salt, 14.8 mg, 41% yield). MS (ESI) m/z 489.5.

Example 37 Preparation of1-(4-fluorophenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea

Following the procedure described in example 34, reaction of4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]aniline(22 mg, 0.06 mmol) (22 mg, 0.06 mmol, triphosgene (18 mg, 0.06 mmol) and4-fluoroaniline (20 mg, 0.18 mmol) gave the title compound as off-whitesolid (14.8 mg, 49% yield). MS (ESI) m/z 506.5.

Example 38 Preparation of1-[4-(hydroxymethyl)phenyl]-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea

Following the procedure described in example 34, reaction of4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]aniline(22 mg, 0.06 mmol) (22 mg, 0.06 mmol, triphosgene (18 mg, 0.06 mmol) and4-aminobenzyl alcohol (22 mg, 0.18 mmol) gave the title compound asoff-white solid (9.6 mg, 31% yield). MS (ESI) m/z 518.5.

Example 39 Preparation of1-[4-(2-hydroxyethyl)phenyl]-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea

Following the procedure described in example 34, reaction of4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]aniline(22 mg, 0.06 mmol) (22 mg, 0.06 mmol, triphosgene (18 mg, 0.06 mmol) and4-aminophenethyl alcohol (24 mg, 0.18 mmol) gave the title compound asoff-white solid (10.6 mg, 33% yield). MS (ESI) m/z 532.5.

Example 40 Preparation of 2-(diethylamino)ethyl4-[({4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzoate

Following the procedure described in example 34, reaction of4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]aniline(22 mg, 0.06 mmol) (22 mg, 0.06 mmol, triphosgene (18 mg, 0.06 mmol) andprocaine hydrochloride (50 mg, 0.18 mmol) gave the title compound asoff-white solid (1TFA salt, 14.6 mg, 33% yield). MS (ESI) m/z 613.6.

Example 41 Preparation of1-(4-methylphenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea

Following the procedure described in example 34, reaction of4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]aniline(22 mg, 0.06 mmol) (22 mg, 0.06 mmol, triphosgene (18 mg, 0.06 mmol) andp-toluidine (20 mg, 0.18 mmol) gave the title compound as off-whitesolid (9.2 mg, 31% yield). MS (ESI) m/z 502.5.

Example 42 Preparation of1-(4-cyanophenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea

Following the procedure described in example 34, reaction of4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]aniline(22 mg, 0.06 mmol) (22 mg, 0.06 mmol, triphosgene (18 mg, 0.06 mmol) and4-aminobezonitrile (21 mg, 0.18 mmol) gave the title compound asoff-white solid (14.3 mg, 46% yield). MS (ESI) m/z 513.5.

Example 43 Preparation of1-[4-(4-methylpiperazin-1-yl)phenyl]-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea

Following the procedure described in example 34, reaction of4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]aniline(22 mg, 0.06 mmol) (22 mg, 0.06 mmol, triphosgene (18 mg, 0.06 mmol) and4-(4-methylpiperazin-1-yl)aniline (54 mg, 0.18 mmol) gave the titlecompound as off-white solid (2TFA salt, 3.2 mg, 7% yield). MS (ESI) m/z586.6.

Example 44 Preparation of1-isopropyl-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea

Following the procedure described in example 34, reaction of4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]aniline(22 mg, 0.06 mmol) (22 mg, 0.06 mmol, triphosgene (18 mg, 0.06 mmol) andisopropylamine (11 mg, 0.18 mmol) gave the title compound as off-whitesolid (13.6 mg, 50% yield). MS (ESI) m/z 454.5.

Example 45 Preparation of1-(2-hydroxyethyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea

Following the procedure described in example 34, reaction of4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]aniline(22 mg, 0.06 mmol) (22 mg, 0.06 mmol, triphosgene (18 mg, 0.06 mmol) andethanolamine (11 mg, 0.18 mmol) gave the title compound as off-whitesolid (14.4 mg, 53% yield). MS (ESI) m/z 456.5.

Example 46 Preparation of1-[2-(dimethylamino)ethyl]-3-{4-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}urea

MS (ES+) 513.62 (M+H)+.

Example 47 Preparation of1-{4-[4-morpholin-4-yl-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea

MS (ESI) m/z 489.3.

Example 48 Preparation of1-{4-[4-morpholin-4-yl-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea

mp 258° C.; MS (ESI) m/z 489.3.

Following the procedure as outlined in example 1, step 3 the followingcompounds were prepared.

Example 491-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-(2-methylpyridin-4-yl)ureaMS (ESI) m/z 477.3. Example 501-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(2-hydroxyethyl)phenyl]ureaMS (ESI) m/z 506.4 Example 511-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(hydroxymethyl)phenyl]ureaExample 521-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(1-hydroxyethyl)phenyl]ureaMS (ESI) m/z 506.4. Example 531-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(trifluoromethyl)phenyl]ureaMS (ESI) m/z 530.2. Example 541-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-(4-hydroxyphenyl)ureaMS (ESI) m/z 478.2. Example 551-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[5-(trifluoromethyl)pyridin-2-yl]ureaMS (ESI) m/z 530.5. Example 561-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}ureaMS (ESI) m/z 621.54. Example 571-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[3-(1-hydroxyethyl)phenyl]ureaMS (ESI) m/z 506.3. Example 58 methyl4-({[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzoateMS (ESI) m/z 520.3. Example 59 Preparation of1-{4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yloxy)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea

Step 1: To a stirred solution of NaH (50% 460 mg) in dry THFtetrahydro-2H-pyran-4-ol (1.02 g, 10 mmol) was slowly added at roomtemperature. The reaction mixture was stirred at room temperature for 30min and 2,4-dichloro-6-morpholin-4-yl-[1,3,5]triazine (2.35 g, 10 mmol)in THF (50 ml) was slowly added. The reaction mixture was stirred atroom temperature for 48 hours and slowly quenched with ice-cold water.It was extracted with CHCl₃; washed well with water and dried overanhydrous MgSO₄. It was filtered and concentrated and2-chloro-4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yloxy)-1,3,5-triazinewas purified by silica gel column chromatography by eluting it with 40%ethyl acetate:hexane. Yield: 1.5 g, 50%; White solid; mp 91° C.; MS(ESI) m/z 301.52

Step 2:4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yloxy)-1,3,5-triazin-2-yl]anilinewas prepared by the procedure as described in example 1, step 2.Starting from2-chloro-4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yloxy)-1,3,5-triazine(1.5 g, 4.9 mmol) 980 mg (56% yield) of the product was isolated afterpurification using Silica gel column chromatography by eluting it withethyl acetate. Mp. 188° C.; MS (ESI) m/z 358.2.

Step 3:1-{4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yloxy)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylureawas prepared by the procedure as described in example 1, step 3.Starting from4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yloxy)-1,3,5-triazin-2-yl]aniline(212 mg. 0.59 mmol) 190 mg (Yield, 67%) of the final product wasisolated as a white solid. mp 238° C.; MS (ESI) m/z 478.3.

Example 60 Preparation of1-{4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yloxy)-1,3,5-triazin-2-yl]phenyl}-3-phenylurea

1-{4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yloxy)-1,3,5-triazin-2-yl]phenyl}-3-phenylureawas prepared by reacting the4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yloxy)-1,3,5-triazin-2-yl]anilineand the corresponding phenylisocyanate. Product was purified by Gilson,HPLC. MS (ESI) m/z 476.5.

Example 61 Preparation of1-{4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yloxy)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea

1-{4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yloxy)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylureawas prepared by reacting the4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yloxy)-1,3,5-triazin-2-yl]anilineand the corresponding 3-pyridylisocyanate. Product was purified byGilson, HPLC. MS (ESI) m/z 477.53.

Example 62 Preparation of1-[4-(hydroxymethyl)phenyl]-3-{4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yloxy)-1,3,5-triazin-2-yl]phenyl}urea

1-[4-(hydroxymethyl)phenyl]-3-{4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yloxy)-1,3,5-triazin-2-yl]phenyl}ureawas prepared by the triphosgene procedure as described in example 1,step 3. Product was purified by Gilson, HPLC. MS (ESI) m/z 506.6.

Example 63 Preparation of1-(2-methylpyridin-4-yl)-3-{4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yloxy)-1,3,5-triazin-2-yl]phenyl}urea

1-(2-methylpyridin-4-yl)-3-{4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yloxy)-1,3,5-triazin-2-yl]phenyl}ureawas prepared by the triphosgene procedure as described in example 1,step 3. Product was purified by Gilson, HPLC. MS (ESI) m/z 491.5.

Example 64 Preparation of1-[2-(methylamino)ethyl]-3-{4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yloxy)-1,3,5-triazin-2-yl]phenyl}urea

1-[2-(methylamino)ethyl]-3-{4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yloxy)-1,3,5-triazin-2-yl]phenyl}ureawas prepared by the triphosgene procedure as described in example 1,step 3. Product was purified by Gilson, HPLC. MS (ESI) m/z 457.54.

Example 65 Preparation of1-(3-acetylphenyl)-3-{4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yloxy)-1,3,5-triazin-2-yl]phenyl}urea

1-(3-acetylphenyl)-3-{4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yloxy)-1,3,5-triazin-2-yl]phenyl}ureawas prepared by reacting the4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yloxy)-1,3,5-triazin-2-yl]anilineand the corresponding 3-acetylisocyanate. Product was purified byGilson, HPLC. MS (ESI) m/z 518.58.

Example 66 Preparation of1-[4-(dimethylamino)phenyl]-3-{4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yloxy)-1,3,5-triazin-2-yl]phenyl}urea

1-[4-(dimethylamino)phenyl]-3-{4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yloxy)-1,3,5-triazin-2-yl]phenyl}ureawas prepared by reacting the4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yloxy)-1,3,5-triazin-2-yl]anilineand the corresponding 4-(N,N-dimethyl amino)phenylisocyanate. Productwas purified by Gilson, HPLC. MS (ESI) m/z 519.61.

Example 67 Preparation of4-[3-{4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl}ureido]benzoic acid

To a stirred mixture of methyl4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)ureido)benzoate (1.4g, 2.69 mmol), THF (10 mL), MeOH (5 mL) and H₂O (2.5 mL) was addedLiOH.H2O (339 mg, 8.07 mmol) then heated under reflux for 8 hrs.Concentrated and added H₂O (5 mL) then acidified with 2N HCl. The solidwas filtered washed with H₂O and dried to give the product as a tansolid (1.3 g, 96% yield); MS (ESI) m/z=506.3

Example 68 Preparation ofN-(2-(dimethylamino)ethyl)-4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)ureido)benzamide

To a stirred solution of4-[3-{4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl}ureido]benzoic acid(150 mg; 0.297 mmol), Hunig's base (303 L, 1.782 mmol), HBTU (563 mg,1.485 mmol) in 2 mL of NMP was stirred for 1 hr. at room temperature andadded N′,N′-dimethylethane-1,2-diamine (130 μL, 1.188 mmol) then stirredovernight. Added CH₂Cl₂ (40 mL) and washed with sat. NaHCO₃ and H2O.Concentrated and purified by silica gel chromatography CH₂Cl₂:MeOH:7NNH₃ in MeOH (10:1:0.22) to give the product as a white solid (98 mg, 57%yield); MS (ESI) m/z=576.4.

Example 68 PreparationN-(2-(dimethylamino)ethyl)-4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)ureido)benzamideas an HCl salt

To theN-(2-(dimethylamino)ethyl)-4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)ureido)benzamide(72 mg, 0.125 mmol) and MeOH (1 mL) was added 4N HCl in dioxane (1 mL)and stirred for 3 hrs. The solid was filtered and washed with ether togive the product as a white solid (73 mg, yield=95%); MS (ESI)m/z=576.4.

Example 69 Preparation of1-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazine-1-carbonyl)phenyl)ureahydrochloride

To a stirred solution of4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)ureido)benzoic acid(150 mg; 0.297 mmol), Hunig's base (303 μL, 1.782 mmol), HBTU (563 mg,1.485 mmol) in 2 mL of NMP was reacted according to example 68 with1-methylpiperazine (132 L, 1.188 mmol) to give1-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazine-1-carbonyl)phenyl)ureaas a white solid (95 mg, 54% yield); MS (ESI) m/z=588.4.

To a1-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazine-1-carbonyl)phenyl)urea(70 mg, 0.119 mmol) and MeOH (1 mL) was added 4N HCl in Dioxane (1 mL),stirred for 3 hrs. The solid was filtered and washed with ether to givethe product as a white solid (74 mg, yield=100%).

Example 70 Preparation of4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)ureido)-N-methylbenzamide

To the stirred solution of4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)ureido)benzoic acid(150 mg; 0.297 mmol), Hunig's base (303 μL, 1.782 mmol), HBTU (563 mg,1.485 mmol) in 2 mL of NMP was reacted according to example 68 withmethylamine (594 μL, 2M solution. in THF) to give the product as a whitesolid (118 mg, 77% yield); MS (ESI) m/z=519.3.

Example 71 Preparation ofN-(2-(dimethylamino)ethyl)-4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)ureido)-N-methylbenzamidehydrochloride

To the stirred solution of4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)ureido)benzoic acid(150 mg; 0.297 mmol), Hunig's base (303 μL, 1.782 mmol), HBTU (563 mg,1.485 mmol) in 2 mL of NMP was reacted according to example 68 withN1,N1,N2-trimethylethane-1,2-diamine (154 μL, 1.188 mmol) to giveN-(2-(dimethylamino)ethyl)-4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)ureido)-N-methylbenzamideas a white solid (88 mg, 50% yield); MS (ESI) m/z=590.2.

To theN-(2-(dimethylamino)ethyl)-4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)ureido)-N-methylbenzamide(55 mg, 0.127 mmol) and MeOH (1 mL) was added 4N HCl in Dioxane (1 mL)and stirred for 3 hrs. The solid was filtered and washed with ether togive the product as a white solid (70 mg, yield=88%).

Example 72 Preparation of1-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-morpholinopiperidine-1-carbonyl)phenyl)urea

To the stirred solution of4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)ureido)benzoic acid(50 mg; 0.099 mmol), Hunig's base (103 μL, 0.594 mmol), HBTU (188 mg,0.495 mmol) in 1 mL of NMP was reacted according to example 68 with4-(piperidin-4-yl)morpholine (67 mg, 0.396 mmol). Evaporated the solventand purified by HPLC to give the product (40.1 mg, 62% yield); MS (ESI)m/z=658.7.

Example 73 Preparation of4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)ureido)-N-(quinuclidin-3-yl)benzamide

To the solution of4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)ureido)benzoic acid(50 mg; 0.099 mmol), Hunig's base (103 μL, 0.594 mmol), HBTU (188 mg,0.495 mmol) in 2 mL of NMP was reacted according to according to example68 with quinuclidin-3-amine (79 mg, 0.396 mmol). Evaporated the solventand purified by HPLC to give the product (24.3 mg, 40% yield); MS (ESI)m/z=614.7.

Example 74 Preparation of1-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(pyrrolidin-1-yl)piperidine-1-carbonyl)phenyl)urea

To the solution of4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)ureido)benzoic acid(50 mg; 0.099 mmol), Hunig's base (103 μL, 0.594 mmol), HBTU (188 mg,0.495 mmol) in 2 mL of NMP was reacted according to example 68 with4-[1-pyrrolidinyl]piperidine (61 mg, 0.396 mmol). Evaporated the solventand purified by HPLC to give the product as a white solid (37 mg, 58%yield); MS (ESI) m/z=642.7

Example 75 Preparation of1-(4-(1,4′-bipiperidine-1′-carbonyl)phenyl)-3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)urea

To the solution of4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)ureido)benzoic acid(50 mg; 0.099 mmol), Hunig's base (103 μL, 0.594 mmol), HBTU (188 mg,0.495 mmol) in 2 mL of NMP was reacted according to example 68 with1,4′-bipiperidine (67 mg, 0.396 mmol). Evaporated the solvent andpurified by HPLC to give the product as a white solid (39 mg, 60%yield); MS (ESI) m/z=656.8.

Example 76 Preparation of1-(4-(4-(dimethylamino)piperidine-1-carbonyl)phenyl)-3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)urea

To the solution of4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)ureido)benzoic acid(50 mg; 0.099 mmol), Hunig's base (103 μL, 0.594 mmol), HBTU (188 mg,0.495 mmol) in 2 mL of NMP was reacted according to example 68 withN,N-dimethylpiperidin-4-amine (51 mg, 0.396 mmol). Evaporated thesolvent and purified by HPLC to give the product (30.6 mg, 52% yield);MS (ESI) m/z=616.7.

Example 77 Preparation of1-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(piperazine-1-carbonyl)phenyl)urea

To the solution of4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)ureido)benzoic acid(50 mg; 0.099 mmol), Hunig's base (103 μL, 0.594 mmol), HBTU (188 mg,0.495 mmol) in 2 mL of NMP was reacted according to example 68 withpiperazine (34 mg, 0.396 mmol). Evaporated the solvent and purified byHPLC to give the product (17.2 mg, 30% yield); MS (ESI) m/z=573.6

Example 78 Preparation of1-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-(pyridin-2-yl)acetyl)phenyl)urea

To the solution of4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)ureido)benzoic acid(50 mg; 0.099 mmol), Hunig's base (103 μL, 0.594 mmol), HBTU (188 mg,0.495 mmol) in 2 mL of NMP was reacted according to example 68 withpyridin-2-ylmethanamine (43 mg, 0.396 mmol). Evaporated the solvent andpurified by HPLC to give the product (9 mg, 15% yield); MS (ESI)m/z=596.6.

Preparation of3-(4,6-dichloro-1,3,5-triazin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane

To a solution of cyanuric chloride (2.00 g, 10.85 mmoles) in acetone (20mL) and water (10 mL) at 0° C. was added a solution of8-oxa-3-azabicyclo[3.2.1]octane hydrochloride (1.46 g, 9.76 mmoles) insaturated aqueous NaHCO₃ (25 mL) and acetone (25 mL) via addition funnelover 15 minutes. The reaction was stirred at 0° C. for 2 hours, thenfiltered to collect a white precipitate. The precipitate was washed withwater (25 mL) and dried. The crude product was purified by columnchromatography (30:70 ethyl acetate in hexanes) to provide3-(4,6-dichloro-1,3,5-triazin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane(1.55 g) as a white solid.

Procedure to prepare 3-(4-chloro-6-(substitutedamino)-1,3,5-triazin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane

To a solution of3-(4,6-dichloro-1,3,5-triazin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane(0.085 g, 0.33 mmoles) and Na₂CO₃ (0.041 g, 0.39 mmoles) in acetone (1mL) and water (1 mL) was added the desired amine (0.36 mmoles). Thesolution was heated to 55° C. and stirred for 2 hours then concentratedto provide crude amino-triazine, which was used directly withoutpurification. Following this procedure, the following compounds wereprepared.

-   3-(4-chloro-6-(piperidin-1-yl)-1,3,5-triazin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane

(310.3, M+H).

-   3-(4-chloro-6-(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane

(296.3, M+H)

-   t-butyl    2-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-chloro-1,3,5-triazin-2-ylamino)ethylcarbamate

(385.3, M+H).

-   2-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-chloro-1,3,5-triazin-2-ylamino)ethanol

(286.3, M+H).

-   4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-chloro-N-phenyl-1,3,5-triazin-2-amine

(318.3, M+H).

-   4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-chloro-N-cyclohexyl-1,3,5-triazin-2-amine

(324.3, M+H).

-   t-butyl    3-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-chloro-1,3,5-triazin-2-ylamino)azetidine-1-carboxylate

(397.3, M+H).

Method to prepare4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(substitutedamino)-1,3,5-triazin-2-yl)aniline

A suspension of bis-amino triazine chloride (0.33 mmoles) in toluene (2mL), ethanol (2 mL), and 2M aqueous Na₂CO₃ (0.700 mL) in a microwavevial was sparged with N₂ for 5 minutes. Pd(PPh₃)₄ (0.021 mgs, 0.018mmoles) and 4-aminophenylboronic acid pinacol ester (0.094 mgs, 0.43mmoles) were added and the vial was sealed and heated to 110° C. for 1hour. The mixture was cooled and filtered through Celite™. The filtercake was washed with ethyl acetate and the filtrate was washed withbrine, dried, and concentrated. The crude material was purified by HPLC(Waters system, 5-70% CH₃CN in H₂O w/0.05% NH₄OH) to provide thearyl-substituted triazine compounds. Following this procedure, thefollowing compounds were prepared.

-   4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(piperidin-1-yl)-1,3,5-triazin-2-yl)aniline

(367.4, M+H).

-   4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)aniline

(353.3, M+H).

-   2-(4-(4-aminophenyl)-6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1,3,5-triazin-2-ylamino)ethanol;

(343.3, M+H).

-   4-(4-aminophenyl)-6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-N-phenyl-1,3,5-triazin-2-amine;

(375.3, M+H).

-   4-(4-aminophenyl)-6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-N-cyclohexyl-1,3,5-triazin-2-amine;

(381.4, M+H).

-   t-butyl    3-(4-(4-aminophenyl)-6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1,3,5-triazin-2-ylamino)azetidine-1-carboxylate;

(454.4, M+H).

Procedure to prepare1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(substitutedamino)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea

A solution of triphosgene (0.034 mgs, 0.114 mmoles) in CH₂Cl₂ (1 mL) wasprepared. A solution of the desired triazine aniline derivative (0.23mmoles) in CH₂Cl₂ (1 mL) and triethylamine (0.095 mL, 0.68 mmoles) wasadded and the reaction was allowed to stir at room temperature for 15minutes. A solution of 4-aminopyridine (0.043 mgs, 0.46 mmoles) in THF(1 mL) was then added and the solution was stirred at room temperaturefor 3 hours, then concentrated and purified by HPLC (Waters system,5-70% CH₃CN in H₂O w/0.05% NH₄OH) to provide the1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(substitutedamino)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea derivatives. Thefollowing compounds were prepared by this procedure:

Example 79 Preparation of1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(piperidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea

487.2, M+H.

Example 80 Preparation of1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea

474.2, M+H.

Example 81 Preparation of1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(1-hydroxyethyl)phenyl]urea

To a stirred mixture of4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline (0.140, 0.40 mmoles)in methylene chloride at 0° C. was added triphosgene (0.25, 0.84 mmoles)and Et₃N (3 mL). The reaction mixture was stirred for 20 minutes at 0°C. Then 1-(4-aminophenyl)ethanol (0.10 g, 0.73 mmoles) was added to themixture. The reaction mixture was stirred for about 16 hours at roomtemperature. The solvent was removed. The residue was dissolved in DMSOand place at HPLC using acetonitrile buffer TFA to give 48 mg (24%) of[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(1-hydroxyethyl)phenyl]urea.M+H 506.4.

Example 82 Preparation of1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-(2-methylpyridin-4-yl)urea

Starting from 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline (0.140,0.40 mmoles) and 2-methyl-4-aminopyridine (80 mg, 0.73 mmol) andfollowing the procedure as outlined in Example 81,1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-(2-methylpyridin-4-yl)ureawas isolated by HPLC purification. Yield: 60 mg, 27%; MS (ESI)m/z=477.3.

Example 83 Preparation of1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(hydroxymethyl)phenyl]urea

Starting from 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline (0.140,0.40 mmoles) and 4-aminophenylmethanol (100 mg, 0.81 mmol) and followingthe procedure described in example 81,1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(hydroxymethyl)-phenyl]ureawas isolated by HPLC purification. Yield: 58 mg, 26%; MS (ESI)m/z=492.3.

Example 84 Preparation of1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-hydroxyphenyl]urea

Starting from 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline (0.140,0.40 mmoles) and 4-aminophenol (89 mg, 0.81 mmol) and following theprocedure as outlined in example 81,1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-hydroxyphenyl]ureawas isolated by HPLC purification. Yield: 62 mg, 16%; MS (ESI)m/z=478.2.

Example 85 Preparation of1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(trifluoromethyl)phenyl]urea

Starting from 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline (0.140,0.40 mmoles) and 4-trifluoromethylaniline (100 mg, 0.62 mmol) andfollowing the procedure as outlined in example 81,1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(trifluoromethyl)phenyl]ureawas isolated by HPLC purification. Yield: 25 mg, 13%; MS (ESI)m/z=430.2.

Example 86 Preparation of1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}urea

Starting from 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline (0.140,0.40 mmoles) and 4-trifluoromethylaniline (140 mg, 0.40 mmol) andfollowing the procedure as outlined in example 81,1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}ureawas isolated by HPLC purification. Yield: 40 mg, 16%; MS (ESI)m/z=628.3.

Example 87 Preparation of1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[5-(trifluoromethyl)pyridin-2-yl]urea

Starting from 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline (0.160,0.47 mmoles) and 2-amino-5-trifluorophenylpyridine (100 mg, 0.61 mmol)and following the procedure as outlined in example 81,1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[5-(trifluoromethyl)pyridin-2-yl]ureawas isolated by HPLC purification. Yield: 10 mg, 4.1%; MS (ESI)m/z=531.3.

Example 88 Preparation of1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[3-(1-hydroxyethyl)phenyl]urea

Starting from 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline (0.160,0.47 mmoles) and 1-(3-aminophenyl)ethanol (100 mg, 0.73 mmoles)andfollowing the procedure as outlined in example 81,1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[3-(1-hydroxyethyl)phenyl]ureawas isolated by HPLC purification. Yield: 10 mg, 4.1%; MS (ESI)m/z=531.3.

Example 89 Preparation of1-(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylureaStep 1: Preparation of2-chloro-4-[(3S)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazine

To a stirred solution of dichloromonomorpholino derivative of1,3,5-triazine (2.0 g, 8.5 mmoles) in methylene chloride 200 mL, wasadded 3S-3-methylmorpholine (0.85 g, 8.5 mmoles) combined with twoequivalents of triethylamine 1.7 mL dropwise manner. After the additionreaction mixture was stirred at room temperature for 3 hours andquenched with water. The aqueous layer was washed well with water; driedover anhydrous MgSO₄ and filtered. The solvent was evaporated and theresidue obtained was triturated with diethyl ether/hexane (1:1) andfiltered. The solid was used without further purification. (1.0 g, 40%yield). M+H 357.3.

Step 2: Preparation of4-{4-[(3S)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}aniline

A mixture of2-chloro-4-[(3S)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazine(1.26, 4.2 mmol), sodium carbonate solution (2M, 2 mL), tetrakispalladium triphenylphosphine 70 mg (catalytic amount) and 4-aminophenylboronic pinacol ester (1.37 g, 6.3 mmoles) in DME (100 mL) was heated toreflux for 24 hours. The solvent was evaporated, the residue wasre-dissolved in methylene chloride and filtered through Celite™. Thesolvent was evaporated and the residue was chromatographed on silica geleluting with first 26/4 hexanes/ethyl acetate then increased to 1/1hexanes ethyl acetate to give 1.0 of4-{4-[(3S)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}aniline(71% yield); M+H 357.2.

Step 3: Preparation of1-(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea

Starting from4-{4-[(3S)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}aniline(0.160, 0.44 mmoles) and 4-aminopyridine (100 mg, 1.06 mmoles) andfollowing the procedure as outlined in example 81,1-(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylureawas isolated by HPLC purification. Yield: 125 mg, 60%; MS (ESI) m/z477.3.

Example 90 Preparation of1-[4-(2-hydroxyethyl)phenyl]-3-(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)urea

Starting from4-{4-[(3S)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}aniline(0.160, 0.44 mmoles) and 4-(1-hydroxyethyl)aniline (137 mg, 1 mmole)andfollowing the procedure described in example 81,1-[4-(2-hydroxyethyl)phenyl]-3-(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)ureawas isolated by HPLC purification. Yield: 125 mg, 60%; MS (ESI) m/z519.6

Example 91 Preparation of1-[4-(2-hydroxymethyl)phenyl]-3-(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)urea

Starting from4-{4-[(3S)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}aniline(0.160, 0.44 mmoles) and 4-aminophenylmethanol (0.10 g, 0.81 mmoles) andfollowing the procedure as outlined in example 81,1-[4-(2-hydroxymethyl)phenyl]-3-(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)ureawas isolated by HPLC purification. Yield: 55 mg, 16%; MS (ESI) m/z506.3.

Example 92 Preparation of1-(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-(2-methylpyridin-4-yl)urea

Starting from4-{4-[(3S)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}aniline(0.160, 0.44 mmoles) and 2-methyl-4-aminopyridine (0.10 g, 0.92 mmoles)and following the procedure as outlined in example 81,1-(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-(2-methylpyridin-4-yl)ureawas isolated by HPLC purification. Yield: 75 mg, 36%; MS (ESI) m/z491.3.

Example 93 Preparation of1-[4-(1-hydroxyethyl)phenyl]-3-(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)urea

Starting from4-{4-[(3S)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}aniline(0.160, 0.44 mmoles) and 1-(4-aminophenyl)ethanol (126 mg, 0.92 mmoles)and following the procedure as outlined in example 81,1-[4-(1-hydroxyethyl)phenyl]-3-(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)ureawas isolated by HPLC purification. MS (ESI) m/z 519.6.

Example 94 Preparation of1-[4-(4-isopropoxy-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-pyridin-4-ylurea

Step 1: To a stirred solution of isopropanol (250 mg, 4.1 mmol) in dryTHF (50 ml) at −78° C., n-butyllithium (2.6 ml, 1.6 mol solution) wasslowly added. The reaction mixture was stirred for 30 minutes and asolution of 2,4-dichloro-6-morpholin-4-yl-[1,3,5]triazine (1.00 g, 4.25mmol) in THF was added to the solution. The reaction mixture was stirredat room temperature for 24 hours and quenched with water and extractedwith DCM. The crude product obtained was taken to next step withoutpurification.

Step 2: A mixture of (crude)4-(chloro-6-isopropoxyl-1,2,3-triazin-2-yl)morpholine of (2.91 g, 11.27mmol) 4-amino-phenylboronic acid pinacol ester (3.59 g, 16.4 mmoles),tetrakis palladium triphenylphosphine (120 mg catalytic amount) andsodium carbonate solution (2M, 2 mL) was refluxed in DME (100 mL) for 24hours. The solvent was removed and the residue was re-dissolved inmethylene chloride and filtered through Celite™. The solvent wasevaporated and the residue was chromatographed on silica gel elutingwith first 26:4 hexane:ethyl acetate then increased to 1/1 hexanes ethylacetate to give 0.65 g (yield 18%) of4-(4-isopropoxy-6-morpholino-1,3,5-triazin-2-yl)aniline. M+H 316.3.

Step 3: Starting from4-(4-isopropoxy-6-morpholino-1,3,5-triazin-2-yl)aniline (0.140, 0.44mmoles) and 4-aminopyridine (100 mg, 1.06 mmoles) and following theprocedure as outlined in example 81,1-[4-(4-isopropoxy-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-pyridin-4-ylureawas isolated by HPLC purification. Yield: 15 mg, 7.8%; MS (ESI)m/z=436.3.

Example 95 Preparation of methyl4-({[4-(4-isopropoxy-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzoate

A mixture of 4-(4-isopropoxy-6-morpholino-1,3,5-triazin-2-yl)aniline(1.3 g, 4.1 mmol), triethylamine (2 ml) and4-carbomethoxy-phenylisocyanate (1451 mg, 8.2 mmol) was stirred for 48hours and quenched with water and washed well. The organic layer wasdried and filtered. It was concentrated and purified by columnchromatography by eluting it initially with 10% ethyl acetate:hexane andlatter with 40% ethyl acetate:hexane. White solid; 600 mg, 30%; MS (ESI)m/z 492.5.

Example 96 Preparation of1-[4-(4-isopropoxy-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}urea

Starting from methyl4-({[4-(4-isopropoxy-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzoicacid (160 mg, 0.33 mmol) and 4-methylpiperazine following the procedureas outlined in Experimental 71, 80 mg (44% Yield) of the titled compoundwas isolated as white solid. MS (ESI) m/z 281.2.

Example 97 Preparation of4-({[4-(4-isopropoxy-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)-N-(1-methylpiperidin-4-yl)benzamide

Starting from methyl4-({[4-(4-isopropoxy-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzoicacid (200 mg, 0.42 mmol) and 4-amino-1-methylpiperidine following theprocedure as outlined in Experimental 71, 65 mg (27% Yield) of thetitled compound was isolated as white solid. MS (ESI) m/z 574.68.

Example 98 Preparation of1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-(1-methylpiperidin-4-yl)urea

Starting from 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline (140 mg0.40 mmoles) and 4-amino-1-methylpiperidine (70 mg, 0.62 mmol) andfollowing the procedure as outlined in example 1, step 3, 20 mg (10%Yield) of the final compound was isolated as a solid. MS (ESI) m/z=483.4

Example 99 Preparation of1-(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-(1-methylpiperidin-4-yl)urea

Starting from4-{4-[(3S)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}aniline(0.140, 0.39 mmoles) and 4-amino-1-methylpiperidine (70 mg, 0.62 mmol)and following the procedure as outlined in example 81, the titledproduct was prepared and purified by HPLC. Yield: 120 mg, 40%; 497.4.

Example 100 Preparation of1-{4-[4-(3,6-Dihydro-2H-pyran-4-yl)-6-morpholin-4-yl-[1,3,5]triazin-2-yl]-phenyl}-3-pyridin-4-yl-ureaStep 1: Preparation of2-Chloro-4-(3,6-dihydro-2H-pyran-4-yl)-6-morpholin-4-yl-[1,3,5]triazine

In a three necked flask under nitrogen equipped was dissolved2,4-dichloro-6-morpholin-4-yl-[1,3,5]triazine (610 mg, 2.6 mmol),tributyldihydropyranylstannane (1.45 g, 3.89 mmol, 1.5 eq), and(Ph₃P)₂PdCl₂ (150 mg, 0.21 mmol, 0.1 eq) in anhydrous dioxan (5 ml). Thereaction mixture was heated under stirring to 90° C. for 16 hrs. Forpurification silica gel (10 g) was added to the mixture and the solventwas removed to let the product adsorbed on the silica gel. The silicagel plug was placed on a column and the mixture was flashchromatographed with hexane:ethyl acetate (10:1) to give after removalsolvent the product as off white solid (345 mg=47% yield); MS (ESI) m/z281.

Step 2: Preparation of4-[4-(3,6-Dihydro-2H-pyran-4-yl)-6-morpholin-4-yl-[1,3,5]triazin-2-yl]-phenylamine

To a microwave processing tube was added dimethoxyethane (4 mL), aqueousNa₂CO₃ (2 molar)(1 mL, 2 mmol, 2 eq), (Ph₃P)₄Pd (101 mg, 0.088 mmol),4-anilinoboronic acid or ester (581 mg, 2.65 mmol, 1.5 eq) and the2-chloro-4-(3,6-dihydro-2H-pyran-4-yl)-6-morpholin-4-yl-[1,3,5]triazine(500 mg, 1.76 mmol) and the vessel was sealed. The mixture was heated to140° C. for 60 minutes. The solvents were distilled and the crudecompound was purified by silica gel chromatography using CH₂Cl₂/ethylacetate (10:1) and later CH₂Cl₂/MeOH/NH₃ (20:1:0.1) to give the productas a off-white solid (520 mg, 87% yield); MS (ESI) m/z 340.2

Step 3: Preparation of1-{4-[4-(3,6-Dihydro-2H-pyran-4-yl)-6-morpholin-4-yl-[1,3,5]triazin-2-yl]-phenyl}-3-pyridin-4-yl-urea

To a stirred solution of triphosgene (140 mg, 0.47 mmol) in CH₂Cl₂ (6mL) was added4-[4-(3,6-dihydro-2H-pyran-4-yl)-6-morpholin-4-yl-[1,3,5]triazin-2-yl]-phenylamine(200 mg, 0.59 mmol) at 25° C. The reaction mixture was stirred for 15min and 4-aminopyridine (166 mg, 1.77 mmol) and NEt₃ (814 μL, 5.89 mmol)were added and the reaction mixture was stirred for additional 1 hr. Thesolvents were distilled and the crude mixture was purified bysemi-prep-HPLC (TFA-method) to give1-{4-[4-(3,6-dihydro-2H-pyran-4-yl)-6-morpholin-4-yl-[1,3,5]triazin-2-yl]-phenyl}-3-pyridin-4-yl-urea(75 mg, 22% yield); MS (ESI) m/z 460

Example 101 Preparation of1-{4-[4-Morpholin-4-yl-6-(tetrahydro-pyran-4-yl)-[1,3,5]triazin-2-yl]-phenyl}-3-pyridin-4-yl-urea

1-{4-[4-(3,6-dihydro-2H-pyran-4-yl)-6-morpholin-4-yl-[1,3,5]triazin-2-yl]-phenyl}-3-pyridin-4-yl-urea(130 mg, 0.28 mmol) and Pd—C (10%, wet) (113 mg) were suspended inmethanol/THF/CH₂Cl₂ (4:1:1) (30 mL) and hydrogenated (at 1 atm pressure)for 3 h. After completion, the catalyst was removed by filtration overCelite™ and the solvents were removed in vacuo to obtain the crudeproduct, which was purified by semi-prep-HPLC (TFA-method), to give (32mg=20% yield) of1-{4-[4-Morpholin-4-yl-6-(tetrahydro-pyran-4-yl)-[1,3,5]triazin-2-yl]-phenyl}-3-pyridin-4-yl-urea;MS (ESI) m/z 462.

Example 102 Preparation of1-{4-[4-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy)-6-morpholin-4-yl-[1,3,5]triazin-2-yl]-phenyl}-3-pyridin-4-yl-ureaStep 1: Preparation of3-(4-Chloro-6-morpholin-4-yl-[1,3,5]triazin-2-yloxy)-8-methyl-8-aza-bicyclo[3.2.1]octane

In a three neck flask equipped with stirring bar under N₂ atmospheretropine (1 g, 4.24 mmol) was suspended in (anhydrous) THF (15 mL). Themixture was cooled to −78° C. and BuLi (2M in THF) (5.53 ml, 1.2 eq) wasadded dropwise and the mixture was allowed to warm to 25° C. over 30minutes. To the reaction mixture2,4,-dichloro-6-morpholin-4-yl-[1,3,5]triazine (996 mg, 4.24, mmole) wasadded and allowed to stir overnight. For work up, ether (100 mL) wasadded. The organic layer was washed with water (20 mL) and brine (20 mL)and dried over MgSO₄, filtered and the solvents were removed to obtain acolorless oil. Further purification by flash-chromatography usingCH₂Cl₂/MeOH/NH₃ (15:1:0.1) gave the product as white solid (600 mg, 42%yield); MS (ESI) m/z 340

Step 2: Preparation of4-[4-(8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy)-6-morpholin-4-yl-[1,3,5]triazin-2-yl]-phenylamine

To a microwave processing tube was added dimethoxyethane (4 mL), aqueousNa₂CO₃ (2 molar)(1 mL, 2 mmol, 2 eq), (Ph3P)4Pd (85 mg, 0.074 mmol),4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (482 mg,2.21 mmol, 1.5 eq) and the3-(4-chloro-6-morpholin-4-yl-[1,3,5]triazin-2-yloxy)-8-methyl-8-aza-bicyclo[3.2.1]octane(500 mg, 1.47 mmol) and the vessel was sealed. The mixture was heated to140° C. for 60 minutes. The solvents were distilled and the crudecompound was purified by silica gel chromatography using CH₂Cl₂/ethylacetate (10:1) and later with CH₂Cl₂/MeOH/NH₃ (10:1:0.1) to give theproduct as an off-white solid (300 mg, 51% yield); MS (ESI) m/z 369.

Step 3: Preparation of1-{4-[4-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy)-6-morpholin-4-yl-[1,3,5]triazin-2-yl]-phenyl}-3-pyridin-4-yl-urea

To a stirred solution of triphosgene (60 mg, 0.20 mmol) in CH₂Cl₂ (3 mL)was added4-[4-(8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy)-6-morpholin-4-yl-[1,3,5]triazin-2-yl]-phenylamine(100 mg, 0.25 mmol) at 25° C. The reaction mixture was stirred for 15min and 4-aminopyridine (70 mg, 0.75 mmol) and NEt₃ (346 μL, 2.5 mmol)were added and the reaction mixture was stirred for additional 1 hr. Thesolvents were removed and the crude mixture was purified bysemi-prep-HPLC(NH3-method) to give1-{4-[4-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy)-6-morpholin-4-yl-[1,3,5]triazin-2-yl]-phenyl}-3-pyridin-4-yl-urea(28 mg, 22% yield); MS (ESI) m/z 517.

Example 103 Preparation of4-(3-{4-[4-(8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy)-6-morpholin-4-yl-[1,3,5]triazin-2-yl]-phenyl}-ureido)-benzamide

To a stirred solution of triphosgene (120 mg, 0.40 mmol) in CH₂Cl₂ (3mL) was added4-[4-(8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy)-6-morpholin-4-yl-[1,3,5]triazin-2-yl]-phenylamine(200 mg, 0.5 mmol) at 25° C. The reaction mixture was stirred for 15 minand 4-aminobenzamide (204 mg, 1.5 mmol) and NEt₃ (692 μL, 5 mmol) wereadded and the reaction mixture was stirred for additional 1 hr. Thesolvents were removed and the crude mixture was purified bysemi-prep-HPLC (NH3-method) to give4-(3-{4-[4-(8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy)-6-morpholin-4-yl-[1,3,5]triazin-2-yl]-phenyl}-ureido)-benzamide(42 mg, 15% yield) MS (ESI) m/z 559.

Example 104 Preparation of3-({4-Morpholin-4-yl-6-[4-(3-pyridin-4-yl-ureido)-phenyl]-[1,3,5]triazin-2-ylamino}-methyl)-azetidine-1-carboxylicacid tert-butyl ester Step 1: Preparation of3-[(4-Chloro-6-morpholin-4-yl-[1,3,5]triazin-2-ylamino)-methyl]-azetidine-1-carboxylicacid tert-butyl ester

To a solution of the 3-aminomethyl-azetidine-1-carboxylic acidtert-butyl ester HCl salt (945 mg, 4.24 mmol) and NEt₃ (856 mg, 8.48mmol) in THF (10 mL) at 0° C. was added a suspension of2,4-dichloro-6-morpholin-4-yl-[1,3,5]triazine (996 mg, 4.24 mmol) at 0°C. The reaction mixture was stirred for another 1 hr at 0° C. andallowed to warm to 20° C. and stirred for 1-4 hrs to drive the reactionto completion. Silica gel (20 g) was added to the reaction mixture andthe solvent was removed so that product was adsorbed on the silica gel.The silica gel plug was placed on top of a column to purify by flashchromatography using CH₂Cl₂/MeOH/NH3 (20:1:01) eluent. After unifyingthe product fraction, and evaporation of solvent, (750 mg, 46% yield)product was obtained as yellow solid; MS (ESI) m/z 385

Step 2: Preparation of3-{[4-(4-Amino-phenyl)-6-morpholin-4-yl-[1,3,5]triazin-2-ylamino]-methyl}-azetidine-1-carboxylicacid tert-butyl ester

To a microwave processing tube was added dimethoxyethane (15 mL),aqueous Na2CO3 (2 molar)(4 mL, 8 mmol, 2 eq), (Ph3P)4Pd (317 mg, 0.55mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine(1.81 g, 8.30 mmol, 1.5 eq) and3-[(4-Chloro-6-morpholin-4-yl-[1,3,5]triazin-2-ylamino)-methyl]-azetidine-1-carboxylicacid tert-butyl ester (1.3 g, 5.53 mmol) and the vessel was sealed. Themixture was heated to 140° C. for 60 minutes. The solvents were removedand the crude compound was purified by silica gel chromatography usingCH₂Cl₂/Ethyl acetate (10:1) and later CH₂Cl₂/MeOH/NH3 (15:1:0.1) to givethe product as a off-white solid (1.3 g, 53% yield).

MS (ESI) m/z=442.

Step 3: Preparation of3-({4-Morpholin-4-yl-6-[4-(3-pyridin-4-yl-ureido)-phenyl]-[1,3,5]triazin-2-ylamino}-methyl)-azetidine-1-carboxylicacid tert-butyl ester

To a stirred solution of triphosgene (269 mg, 0.90 mmol) in CH₂Cl₂ (5mL) was added3-{[4-(4-Amino-phenyl)-6-morpholin-4-yl-[1,3,5]triazin-2-ylamino]-methyl}-azetidine-1-carboxylicacid tert-butyl ester (500 mg, 1.13 mmol) at 25° C. The reaction mixturewas stirred for 15 min and 4-aminopyridine (319 mg, 3.39 mmol) and NEt₃(1.56 mL, 11.3 mmol) were added and the reaction mixture was stirred foradditional 1 hr. The solvents were removed on a rotary evaporator andthe crude mixture was purified by semi-prep-HPLC (TFA-method) to give3-({4-Morpholin-4-yl-6-[4-(3-pyridin-4-yl-ureido)-phenyl]-[1,3,5]triazin-2-ylamino}-methyl)-azetidine-1-carboxylicacid tert-butyl ester (150 mg, 16% yield); MS (ESI) m/z 562.

Example 105 Preparation of1-(4-{4-[(azetidin-3-ylmethyl)-amino]-6-morpholin-4-yl-[1,3,5]triazin-2-yl}-phenyl)-3-pyridin-4-yl-urea

3-({4-Morpholin-4-yl-6-[4-(3-pyridin-4-yl-ureido)-phenyl]-[1,3,5]triazin-2-ylamino}-methyl)-azetidine-1-carboxylicacid tert-butyl ester (100 mg, 0.18 mmol) was dissolved CH₂Cl₂ (1 mL)and TFA (1 mL) was added. It was stirred for 16 hrs at 25° C. and thenthe solvents were removed under reduced pressure and the residue wastreated with acetonitrile/MeOH (1:1) (2 mL) to obtain a white solid,which was collected by filtration to obtain the product as bis-TFA salt(59 mg, 46% yield). MS (ESI) m/z 462.

Example 106 Preparation of Tert-butyl4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-pyridin-4-ylureido)phenyl)-1,3,5-triazin-2-yl)piperazine-1-carboxylate

Tert-butyl 4-(4,6-dichloro-1,3,5-triazin-2-yl)piperazine-1-carboxylatewas prepared according to Löwik, D. W. P. M. and Lowe, C. R. Eur. J.Org. Chem. 2001, 2825-2839.

Step 1: Preparation of tert-butyl4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-chloro-1,3,5-triazin-2-yl)piperazine-1-carboxylate

To a solution of 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride (0.49 g,3.3 mmol) in water (18 mL) was added a suspension of tert-butyl4-(4,6-dichloro-1,3,5-triazin-2-yl)piperazine-1-carboxylate (1.0 g, 3.0mmol) in acetone (about 10 mL). The suspension was stirred magneticallywhile solid sodium carbonate (0.70 g, 6.6 mmol) was added in a singleportion. The mixture was stirred for two hours while heating in a 70-75°C. in an oil bath. After allowing the mixture to cool to roomtemperature, the title compound was removed by filtration, washed withwater, and dried under vacuum.

MS (ES+) 411.0, 412.3 (M+H)+.

Step 2: Preparation of tert-butyl4-(4-(4-aminophenyl)-6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1,3,5-triazin-2-yl)piperazine-1-carboxylate

A suspension of tert-butyl4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-chloro-1,3,5-triazin-2-yl)piperazine-1-carboxylate(1.0 g, 2.4 mmol), 4-aminophenylboronic acid, pinacol ester (0.69 g, 3.2mmol), and tetrakis(triphenylphosphine) palladium (0.28 g, 0.24 mmol) inaqueous 2 M sodium carbonate solution (3 mL) and 1:1 ethanol/toluene (12mL) was irradiated in the microwave at 120° C. for 1 hour. Aftercooling, the biphasic mixture was extracted thrice with ethyl acetate.The extracts were washed with saturated aqueous sodium chloridesolution, dried over anhydrous magnesium sulfate, filtered, andconcentrated to dryness under reduced pressure to give the titlecompound.

MS (ES+) 468.1 (M+H)+.

Step 3: Preparation of tert-butyl4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-pyridin-4-ylureido)phenyl)-1,3,5-triazin-2-yl)piperazine-1-carboxylate

Crude tert-butyl4-(4-(4-aminophenyl)-6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1,3,5-triazin-2-yl)piperazine-1-carboxylate(approx. 1.4 mmol) was dissolved in tetrahydrofuran (20 mL) and thentreated sequentially with triphosgene (0.30 g, 1.0 mmol) andtriethylamine (2 mL). After 5 minutes, the mixture was treated with asolution of 4-aminopyridine (0.53 g, 5.6 mmol) in tetrahydrofuran. Themixture was concentrated under reduced pressure to give crude tert-butyl4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-pyridin-4-ylureido)phenyl)-1,3,5-triazin-2-yl)piperazine-1-carboxylate,a sample of which was purified by reversed phase HPLC to give a puretitle compound.

MS (ES+) 588.2 (M+H)+.

Example 107 Preparation of1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea

Crude tert-butyl4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-pyridin-4-ylureido)phenyl)-1,3,5-triazin-2-yl)piperazine-1-carboxylate(approx 1.4 mmol) was taken up in dichloromethane (20 mL) and treatedwith trifluoroacetic acid (5 mL). The mixture was concentrated underreduced the pressure. To the residue was added diethyl ether to give thetitle compound as a solid di-TFA salt, which was collected by filtrationand dried under house vacuum; MS (ES+) 488.1 (M+H)+.

Example 108 Preparation of1-{4-[4-(4-methylpiperazin-1-yl)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea

1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea-2TFA(115 mg) in 1:198% formic acid and 37% formalin (4 mL) was heated at 75°C. for 90 minutes, then concentrated to dryness and purified on HPLC togive the title compound as its di-TFA salt; MS (ES+) 502.3 (M+H)+.

Example 109 Preparation of1-{4-[4-(4-benzylpiperazin-1-yl)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea

1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea-2TFA(130 mg) in dichloromethane (4 mL) and triethylamine (0.10 mL) wastreated with benzaldehyde (0.10 mL), followed by sodiumtriacetoxyborohydride (80 mg). The mixture was concentrated to drynessand purified on HPLC to give the title compound as its di-TFA salt; MS(ES+) 578.3 (M+H)+.

Example 110 Preparation of1-(4-{4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-[4-(pyridin-3-ylmethyl)piperazin-1-yl]-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea

1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea-2TFA(150 mg) in dichloromethane (4 mL) and triethylamine (0.12 mL) wastreated with 3-pyridinecarboxaldehyde (0.1 mL), followed by sodiumtriacetoxyborohydride (80 mg). The mixture was concentrated to drynessand purified on HPLC to give the title compound as its tri-TFA salt; MS(ES+) 579.3 (M+H)+.

Example 111 Preparation of1-{4-[4-(4-acetylpiperazin-1-yl)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea

1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea-2TFA(230 mg) in dichloromethane (4 mL) and triethylamine (1 mL) was treatedwith acetyl chloride. The mixture was concentrated to dryness andpurified on HPLC to give the title compound as its TFA salt; MS (ES+)530.3 (M+H)+.

Example 112 Preparation of1-(4-{4-[4-(N,N-dimethylglycyl)piperazin-1-yl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea

1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea-2TFA(64 mg) in dichloromethane (4 mL) and triethylamine (1 mL) was treatedwith dimethylaminoacetyl chloride hydrochloride (100 mg). The mixturewas heated with a heat gun, then concentrated to dryness and purified onHPLC to give the title compound as its di-TFA salt; MS (ES+) 573.3(M+H)+.

Example 113 Preparation of1-{4-[4-(4-isonicotinoylpiperazin-1-yl)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea

1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea-2TFA(100 mg) in dichloromethane (4 mL) and triethylamine (1 mL) was treatedwith isonicotinoyl chloride (100 mg). The mixture was concentrated todryness and purified on HPLC to give the title compound as its di-TFAsalt; MS (ES+) 593.1 (M+H)+.

Example 114 Preparation of Methyl4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-{4-[(pyridin-4-ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl]piperazine-1-carboxylate

1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea-2TFA(75 mg) in dichloromethane (2 mL), tetrahydrofuran (2 mL), andtriethylamine (1 mL) was treated with methyl chloroformate (0.10 mL).The mixture was concentrated to dryness and purified on RP-HPLC to givethe title compound as its TFA salt. MS (ES+) 546.3 (M+H)+.

Example 115 Preparation of1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-oxopiperidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)ureaStep 1: Preparation of1-(4,6-dichloro-1,3,5-triazin-2-yl)piperidin-4-one

To magnetically stirred ice-water (72 mL) was added a solution ofcyanuric chloride (2.2 g, 12 mmol) in acetone (48 mL), followed bypiperidone monohydrate hydrochloride (1.8 g, 12 mmol) as a suspension inacetone (20 mL) and water (10 mL). To the mixture was added a suspensionof sodium hydrogen carbonate (2.2 g, 24 mmol) in water (25 mL). Themixture was stirred at 0° C. for two hours. The title compound wascollected by filtration, washed with water, and dried under vacuum.

MS (ES+) 248.8 (M+H)+.

Step 2: Preparation of1-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-chloro-1,3,5-triazin-2-yl)piperidin-4-one

To an aqueous solution of 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride(66 mL) was added 1-(4,6-dichloro-1,3,5-triazin-2-yl)piperidin-4-one(2.7 g, 11 mmol) as a suspension in acetone (40 mL). To the mixture wasadded solid sodium carbonate (2.5 g, 24 mmol). The suspension wasstirred at 80° C. for two hours and then allowed to cool to roomtemperature. The title compound was collected by filtration, washed withwater, and dried under vacuum; MS (ES+) 324.4 (M+H)+.

Step 3: Preparation of1-(4-(4-aminophenyl)-6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1,3,5-triazin-2-yl)piperidin-4-one

A suspension of1-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-chloro-1,3,5-triazin-2-yl)piperidin-4-one(1.0 g, 3.1 mmol), 4-aminophenylboronic acid, pinacol ester (1.0 g, 4.7mmol), and tetrakis(triphenylphosphine) palladium (0.20 g, 0.17 mmol) inaqueous 2 M sodium carbonate solution (3 mL) and 1:1 ethanol/toluene (12mL) was irradiated in the microwave at 120° C. for 1 hour. Aftercooling, the biphasic mixture was extracted thrice with ethyl acetate.The extracts were washed with saturated aqueous sodium chloridesolution, dried over anhydrous magnesium sulfate, filtered, andconcentrated to dryness under reduced pressure to give the titlecompound as a golden yellow foam.

MS (ES+)=381.6 (M+H)+.

Step 4: Preparation of1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-oxopiperidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea

A mixture of crude1-(4-(4-aminophenyl)-6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1,3,5-triazin-2-yl)piperidin-4-one(approx. 3.1 mmol) and triethylamine (4 mL) in dichloromethane (30 mL)was treated with triphosgene (0.71 g, 2.4 mmol). The mixture was thentreated with a solution of 4-aminopyridine (1.8 g, 19 mmol) intetrahydrofuran (20 mL). The mixture was concentrated to dryness underreduced pressure and the residue purified by HPLC to give the titlecompound as its TFA salt. MS (ES+) 501.2 (M+H)+.

Example 116 Preparation of1-{4-[4-(4-hydroxypiperidin-1-yl)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea

1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-oxopiperidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea-TFA(56 mg) was taken up in methanol/tetrahydrofuran (1:1, 6 mL), and themixture at 0° C. was treated with sodium borohydride (10 mg). Afterwarming to room temperature, the mixture was concentrated to a residuewhich then was purified by HPLC to give the title compound as its TFAsalt; MS (ES+) 503.0 (M+H)+.

Example 117 Preparation of1-(4-{4-[4-(benzylamino)piperidin-1-yl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea

1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-oxopiperidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea-TFA(85 mg) in dichloromethane (3 mL) and tetrahydrofuran (3 mL) was treatedwith benzylamine (0.030 mL), followed by glacial acetic acid (0.016 mL)and sodium triacetoxyborohydride (89 mg). After completion of thereaction, methanol was added and mixture was concentrated to dryness.The residue was purified by HPLC to give the title compound as itsdi-TFA salt.

MS (ES+) 592.3 (M+H)+.

Example 118 Preparation of1-(4-{4-[4-(methylamino)piperidin-1-yl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea

1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-oxopiperidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea-TFA(50 mg) in tetrahydrofuran (5 mL) was treated with methylamine (2.0 Msolution in tetrahydrofuran, 0.16 mL), followed by glacial acetic acid(0.009 mL) and sodium triacetoxyborohydride (51 mg). After completion ofthe reaction, methanol was added and mixture was concentrated todryness. The residue was purified by HPLC to give the title compound asits di-TFA salt; MS (ES+) 516.3 (M+H)+.

Example 119 Preparation of1-(4-{4-[4-(ethylamino)piperidin-1-yl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea

1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-oxopiperidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea-TFA(50 mg) in tetrahydrofuran (5 mL) was treated with ethylamine (2.0 Msolution in tetrahydrofuran, 0.16 mL), followed by glacial acetic acid(0.009 mL) and sodium triacetoxyborohydride (51 mg). After completion ofthe reaction, methanol was added and mixture was concentrated todryness. The residue was purified by HPLC to give the title compound asits di-TFA salt; MS (ES+) 530.3 (M+H)+.

Example 120 Preparation of1-{4-[4-(4-{[2-(dimethylamino)ethyl]amino}piperidin-1-yl)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea

The titled compound was prepared by the procedure as outlined in example118, by reacting1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-oxopiperidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea-TFA(50 mg) with N,N-dimethylethylenediamine (0.026 mL) and purified by HPLCand isolated as its tri-TFA salt; MS (ES+) 573.7 (M+H)+.

Example 121 Preparation of1-{4-[4-(4-morpholin-4-ylpiperidin-1-yl)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea

By reacting1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-oxopiperidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea-TFA(50 mg) with 1-(2-aminoethyl)pyrrolidine (0.030 mL) and following theprocedure as mentioned in Experimental 118, the title product wasisolated as its tri-TFA salt; MS (ES+) 599.8 (M+H)+.

Example 122 Preparation of1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea

By reacting1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-oxopiperidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea-TFA(40 mg) and 1-methylpiperazine (0.050 mL) and following the procedure asoutlined in example 118, the titled compound was isolated after HPLCpurification as its tri-TFA salt; MS (ES+) 585.9 (M+H)+.

Example 123 Preparation of1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(2-hydroxyethylamino)piperidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea

Starting from1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-oxopiperidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea-TFA(50 mg) and ethanolamine (0.020 mL) and following the procedure asoutlined in example 118, the title compound was isolated as its di-TFAsalt after HPLC purification. MS (ES+) 546.7 (M+H)+.

Example 124 Preparation of1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(2-morpholinoethylamino)piperidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea

Starting from1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-oxopiperidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea-TFA(50 mg)and 1-(2-aminoethyl)morpholine (0.031 mL) and following theprocedure as outlined in example 118, the titled compound was isolatedas its tri-TFA salt after HPLC purification; MS (ES+) 615.9 (M+H)+.

Example 125 Preparation of Methyl2-(1-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-pyridin-4-ylureido)phenyl)-1,3,5-triazin-2-yl)piperidin-4-ylamino)acetate

Starting from1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-oxopiperidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea-TFA(50 mg) and glycine methyl ester hydrochloride (20 mg) and triethylamine(10 drops) and following the procedure as outlined in example 118 thetitle compound was isolated as its di-TFA salt after HPLC purification;MS (ES+) 574.8 (M+H)+.

Example 126 Preparation of2-(1-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-pyridin-4-ylureido)phenyl)-1,3,5-triazin-2-yl)piperidin-4-ylamino)acetamide

Starting from1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-oxopiperidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea-TFA(50 mg) and glycinamide hydrochloride (18 mg) and triethylamine (10drops) and following the procedure as outlined in example 118 the titlecompound was isolated as its di-TFA salt after HPLC purification; MS(ES+) 559.8 (M+H)+.

Example 127 Preparation of Tert-butyl2-(1-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-pyridin-4-ylureido)phenyl)-1,3,5-triazin-2-yl)piperidin-4-ylamino)acetate

Starting from1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-oxopiperidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea-TFA(60 mg) and glycine tert-butyl ester hydrochloride (33 mg) andtriethylamine (10 drops) and following the procedure as outlined inexample 118, the title compound was isolated as its di-TFA salt afterHPLC purification; MS (ES+) 616.9 (M+H)+.

Example 128 Preparation of2-(1-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-pyridin-4-ylureido)phenyl)-1,3,5-triazin-2-yl)piperidin-4-ylamino)aceticacid

Tert-butyl2-(1-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-pyridin-4-ylureido)phenyl)-1,3,5-triazin-2-yl)piperidin-4-ylamino)acetate(28 mg) in dichloromethane (3 mL) was treated with trifluoroacetic acid(1 mL) and then concentrated to dryness to give the title compound asits TFA salt.

MS (ES+) 560.2 (M+H)+.

Example 129 Preparation of4-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]aniline

MS (ES+) 399.47 (M+H)+.

Example 130 Preparation of1-{4-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea

MS (ES+) 519.58 (M+H)+.

Example 131 Preparation of1-{4-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea

MS (ES+) 519.58 (M+H)+.

Example 132 Preparation of1-{4-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-phenylurea

MS (ES+) 518.59 (M+H)+.

Example 133 Preparation of1-[4-(dimethylamino)phenyl]-3-{4-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}urea

MS (ES+) 561.66 (M+H)+.

Example 134 Preparation of1-(4-cyanophenyl)-3-{4-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}urea

MS (ES+) 543.60 (M+H)+.

Example 135 Preparation of1-{4-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-(2-methylpyridin-4-yl)urea

MS (ES+) 533.61 (M+H)+.

Example 136 Preparation of1-[2-(dimethylamino)ethyl]-3-{4-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}urea

MS (ES+) 513.62 (M+H)+.

Example 137 Preparation of1-[4-(4-morpholin-4-yl-6-quinolin-3-yl-1,3,5-triazin-2-yl)phenyl]-3-pyridin-4-ylurea

HRMS: calcd for C28H24N8O2+H+, 505.20950; found (ESI, [M+H]+Obs'd),505.2098; HRMS: calcd for C28H24N8O2+H+, 505.20950; found (ESI, [M+H]+Calc'd), 505.2095.

Example 138 Preparation of2-(difluoromethyl)-1-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-yl-1,3,5-triazin-2-yl)-1H-benzimidazole

A solution of cyanuric chloride (922 mg, 5 mmol) in acetone (5 mL) wasadded to ice. A solution of 8-oxa-3-azabicyclo[3.2.1]octanehydrochloride (750 mg, 5 mmol) and triethylamine (2.1 mL, 15 mmol) inaqueous acetone was then added. After 20 min the precipitate wascollected to give 1.0 g of a white powder which was a 7:3 mixture of3-(4,6-dichloro-1,3,5-triazine-2,4-diyl)-8-oxa-3-azabicyclo[3.2.1]octaneand3,3′-(6-chloro-1,3,5-triazine-2,4-diyl)bis(8-oxa-3-azabicyclo[3.2.1]octane).Treatment of the mixture (400 mg) with2-(difluoromethyl)-1H-benzo[d]imidazole (146 mg, 0.87 mmol) and K2CO3(967 mg, 7 mmol) in DMF (2.5 mL) for 18 h, followed by addition of8-oxa-3-azabicyclo[3.2.1]octane hydrochloride (150 mg) gave, after 1 h,3,3′-(6-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-1,3,5-triazine-2,4-diyl)bis(8-oxa-3-azabicyclo[3.2.1]octane)after purification by HPLC. (M+H) 475.

Example 139 Preparation of2-(difluoromethyl)-1-[4-morpholin-4-yl-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]-1H-benzimidazole

To a stirred solution of3-(4,6-dichloro-1,3,5-triazine-2,4-diyl)(8-oxa-3-azabicyclo[3.2.1]octane)(2.61 g, 10 mmol) in acetone/ice, morpholine (900 mg, 12 mmol) andtriethylamine (5 ml) was added. The reaction mixture was stirred at roomtemperature for 3 h. Separated white solid was filtered and washed withwater. The crude product obtained was pure enough and taken to next stepwithout purification. Treatment of the mixture (270 mg. 0.87 mmol) with2-(difluoromethyl)-1H-benzo[d]imidazole (146 mg, 0.87 mmol) and K2CO3(967 mg, 7 mmol) in DMF (2.5 mL) for 18 hours gave2-(difluoromethyl)-1-[4-morpholin-4-yl-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]-1H-benzimidazoleafter purification by HPLC. (M+H) 445.

Example 140 Preparation of1-[4-(4-azetidin-1-yl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-pyridin-4-ylurea

mp 212° C.; MS (ESI) m/z 433.3.

Example 141 Preparation of methyl4-({[4-(4-azetidin-1-yl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzoate

mp 212° C.; MS (ESI) m/z 490.2.

Example 142 Preparation of1-[4-(4-isopropoxy-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}urea

MS (ESI) m/z 561.6.

Example 143 Preparation of4-({[4-(4-isopropoxy-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)-N-(1-methylpiperidin-4-yl)benzamide

MS (ESI) m/z 575.6.

Example 144 Preparation of1-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-(2-piperidin-1-ylethoxy)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea

MS (ESI) m/z 531.5.

Example 145 Preparation ofmethyl(4-{4-[4-({[4-(4-methylpiperazin-1-yl)phenyl]carbamoyl}amino)phenyl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)carbamate

MS (ESI) m/z 650.7.

Example 146 Preparation of1-cyclopropyl-3-(4-{4-[4-({[4-(4-methylpiperazin-1-yl)phenyl]carbamoyl}amino)phenyl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)urea

MS (ESI) m/z 675.8.

Example 147 Preparation ofN′,N′″-{[6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazine-2,4-diyl]di-4,1-phenylene}bis{1-[4-(4-methylpiperazin-1-yl)phenyl]urea}

MS (ESI) m/z 809.9.

Example 148 Preparation of1-[4-(4-methylpiperazin-1-yl)phenyl]-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-{4-[(pyridin-4-ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl]phenyl}urea

MS (ESI) m/z 712.8.

Example 149 Preparation of1-(4-{4-[(2-aminoethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-3-ylurea

HRMS: calcd for C23H27N9O2+H+, 462.23605; found (ESI, [M+H]+Obs'd),462.2358.

Example 150 Preparation of1-{4-[4-anilino-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea

HRMS: calcd for C27H26N8O2+H+, 495.22515; found (ESI, [M+H]+Obs'd),495.2249.

Example 151 Preparation of4-({[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)-N-(2-piperidin-1-ylethyl)benzamide

MS (ESI) m/2 308.6; HRMS: calcd for C32H41N9O4+H+, 616.33543; found(ESI, [M+H]+Obs'd), 616.3347; HRMS: calcd for C32H41N9O4+H+, 616.33543;found (ESI, [M+H]+ Calc'd), 616.3354.

Example 152 Preparation of1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(morpholin-4-ylcarbonyl)phenyl]urea

MS (ESI) m/z 575.3; HRMS: calcd for C29H34N8O5+H+, 575.27249; found(ESI, [M+H]+Obs'd), 575.2722; HRMS: calcd for C29H34N8O5+H+, 575.27249;found (ESI, [M+H]+ Calc'd), 575.2725.

Example 153 Preparation of1-(4-{4-[(2-hydroxyethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-3-ylurea

MS (ESI) m/z 463.5.

Example 154 Preparation of1-{4-[4-(azetidin-3-ylamino)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea

MS (ESI) m/z 474.5

Example 155 Preparation of1-(4-{4-[(2-morpholin-4-ylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-3-ylurea

MS (ESI) m/z 532.6.

Example 156 Preparation of1-(4-{4-[(3-aminopropyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-3-ylurea

MS (ESI) m/z 476.5.

Example 157 Preparation of1-(4-{4-[(4-cyclopentylpiperazin-1-yl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-3-ylurea

MS (ESI) m/z 571.7

Example 1581-{4-[4-isopropoxy-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea

MS (ESI) m/z 462.53.

Example 159 Preparation of1-{4-[4-isopropoxy-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-[4-(4-methylpiperazin-1-yl)phenyl]ureaExample 160 Preparation of1-{4-[4-chloro-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea

MS (ESI) m/z 438.8.

Example 161 Preparation of1-[4-(4-methyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-pyridin-4-ylurea

MS (ESI) m/z 391.5.

Example 162 Preparation of methyl4-({[4-(4-methyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzoate

MS (ESI) m/z 449.2.

Example 163 Preparation of1-{4-[4-(3,6-dihydro-2H-pyran-4-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}urea

MS (ESI) m/z 584.7.

Example 164 Preparation of4-({[4-(4-methyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)-N-(1-methylpiperidin-4-yl)benzamide

MS (ESI) m/z 530.63.

Example 165 Preparation ofN-[2-(dimethylamino)ethyl]-N-methyl-4-({[4-(4-methyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzamide

MS (ESI) m/z 518.6.

Example 166 Preparation of1-[4-(4-methyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}urea

MS (ESI) m/z 516.6.

Example 167 Preparation of1-(4-{[3-(dimethylamino)pyrrolidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea

HRMS: calcd for C31H39N9O4+H+, 602.31978; found (ESI, [M+H]+Obs'd),602.3192;

Example 168 Preparation of 1-[4-({4-[2-(dimethylamino)ethyl]piperazin-1-yl}carbonyl)phenyl]-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea

HRMS: calcd for C33H44N10O4+H+, 645.36198; found (ESI, [M+H]+Obs'd),645.3615;

Example 169 Preparation of1-(4-{4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-[(piperidin-4-ylmethyl)amino]-1,3,5-triazin-2-yl}phenyl)-3-pyridin-3-ylurea

MS (ESI) m/z 515.6.

Example 170 Preparation of1-(4-{4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-[(2-piperidin-4-ylethyl)amino]-1,3,5-triazin-2-yl}phenyl)-3-pyridin-3-ylurea

MS (ESI) m/z 529.65.

Example 171 Preparation of1-{4-[4-(3-methylimidazolidin-1-yl)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea

MS (ESI) m/z 487.5.

Example 172 Preparation of1-{4-[4-(3-methyltetrahydropyrimidin-1(2H)-yl)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea

MS (ESI) m/z 501.6

Example 173 Preparation of1-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-(2-piperidin-1-ylethoxy)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea

MS (ESI) m/z 530.6.

Example 174 Preparation of1-(4-{4-[2-methoxy-1-(methoxymethyl)ethoxy]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea

MS (ESI) m/z 521.58

Example 175 Preparation of1-(4-{4-[2-methoxy-1-(methoxymethyl)ethoxy]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-[4-(4-methylpiperazin-1-yl)phenyl]urea

MS (ESI) m/z 618.7

Example 176 Preparation of 2-hydroxyethyl(4-{4-[2-methoxy-1-(methoxymethyl)ethoxy]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)carbamate

MS (ESI) m/z 489.53.

Example 177 Preparation of1-(4-{4-[2-methoxy-1-(methoxymethyl)ethoxy]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-methylurea

MS (ESI) m/z 458.52.

Example 178 Preparation of1-cyclopropyl-3-(4-{4-[2-methoxy-1-(methoxymethyl)ethoxy]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)urea

MS (ESI) m/z 484.56.

Example 179 Preparation of1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-{4-[(4-pyrrolidin-1-ylpiperidin-1-yl)carbonyl]phenyl}urea

MS (ESI) m/z 642.4; HRMS: calcd for C34H43N9O4+H+, 642.35108; found(ESI-FTMS, [M+H]1+), 642.3491;

Example 180 Preparation of1-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-(piperidin-3-ylmethoxy)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea

MS (ESI) m/z 516.61

Examples 181 Preparation of1-{4-[4-(4-aminobutoxy)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea

MS (ESI) m/z 490.57

Examples 182 Preparation of1-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-(2-piperidin-4-ylethoxy)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea

MS (ESI) m/z 530.63

Example 183 Preparation of1-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-(piperidin-4-ylmethoxy)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea

MS (ESI) m/z 516.61

Example 184 Preparation4-({[4-(4-butyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzoicacid

MS (ESI) m/z 476.53

Example 185 Preparation ofN-[2-(dimethylamino)ethyl]-4-({[4-(4-isopropoxy-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)-N-methylbenzamide

MS (ESI) m/z 562.6

Example 186 Preparation of1-[4-(4-butyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-pyridin-4-ylurea

MS (ESI) m/z 433.5

Example 187 Preparation ofN-[2-(dimethylamino)ethyl]-4-({[4-(4-isopropoxy-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzamide

MS (ESI) m/z 548.67.

Example 188 Preparation of methyl4-({[4-(4-butyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzoate

MS (ESI) m/z 490.56.

Example 189 Preparation of1-(4-{4-morpholin-4-yl-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea

HRMS: calcd for C24H26N8O3+H+, 475.22006; found (ESI, [M+H]+Obs'd),475.2201.

Example 190 Preparation of1-{4-[4-(methylamino)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea

MS (ESI) m/z 432.49.

Example 191 Preparation of1-{4-[4-(ethylamino)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea

MS (ESI) m/z 446.52

Example 192 Preparation of1-{4-[4-(dimethylamino)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea

MS (ESI) m/z 446.52.

Example 193 Preparation of1-{4-[4-(isopropylamino)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea

MS (ESI) m/z 460.54

Example 194 Preparation of1-{4-[4-(diethylamino)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea

MS (ESI) m/z 474.57.

Example 195 Preparation of4-({[4-(4-azetidin-1-yl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzoic acid; mp 204° C.; MS (ESI) m/z 476.2 Example 196 Preparation of1-[4-(4-azetidin-1-yl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}urea

mp 170° C.; MS (ESI) m/z 558.2.

Example 197 Preparation of4-({[4-(4-azetidin-1-yl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)-N-[2-(dimethylamino)ethyl]-N-methylbenzamide

MS (ESI) m/z 280.7.

Example 198 Preparation of4-({[4-(4-butyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)-N-[2-(dimethylamino)ethyl]-N-methylbenzamideExample 199 Preparation of1-{4-[4-(1-ethoxyvinyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea

MS (ESI) m/z 447.499.

Example 200 Preparation of1-{4-[4-(2-methoxyethoxy)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea

HRMS: calcd for C22H25N7O4+H+, 452.20408; found (ESI, [M+H]+Obs'd),452.2047;

Example 201 Preparation of1-(diethylcarbamoyl)-4-[({4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]pyridinium

HRMS: calcd for C30H38N9O4+H+, 589.31195; found (ESI, [M+H]⁺), 589.3035;

Example 202 Preparation of1-(4-{4-[ethyl(methyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-3-ylurea

MS (ESI) m/z 460.54.

Example 203 Preparation of1-{4-[4-(sec-butylamino)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea

MS (ESI) m/z 474.57.

Example 204 Preparation of1-{4-[4-{[2-hydroxy-1-(hydroxymethyl)ethyl]amino}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea

MS (ESI) m/z 492.54.

Example 205 Preparation of1-(4-{4-[bis(2-hydroxyethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-3-ylurea

MS (ESI) m/z 506.57

Example 206 Preparation of1-(4-{4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-3-ylurea

MS (ESI) m/z 499.58.

Example 207 Preparation of1-{4-[4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea

MS (ESI) m/z 592.71.

Example 208 Preparation of1-(4-{4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-[(4-piperazin-1-ylphenyl)amino]-1,3,5-triazin-2-yl}phenyl)-3-pyridin-3-ylurea

MS (ESI) m/z 578.68.

Example 209 Preparation of1-[4-(4-acetyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-pyridin-4-ylurea

MS (ESI) m/z 419.406

Example 210 Preparation of1-(4-{4-morpholin-4-yl-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-1,3,5-triazin-2-yl}phenyl)-3-{4-[(4-pyrrolidin-1-ylpiperidin-1-yl)carbonyl]phenyl}urea

MS (ESI) m/z 654.3; HRMS: calcd for C35H43N9O4+H+, 654.35108; found(ESI-FTMS, [M+H]1+), 654.35129;

Example 211 Preparation of methyl4-[({4-[4-(2-methoxyethoxy)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzoate

HRMS: calcd for C25H28N6O6+H+, 509.21431; found (ESI, [M+H]+Obs'd),509.214.

Example 212 Preparation of1-methyl-3-(4-{4-[(1-methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)urea

MS (ESI) m/z 397.48.

Example 213 Preparation of1-cyclopropyl-3-(4-{4-[(1-methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)urea

MS (ESI) m/z 423.52.

Example 214 Preparation of1-(2-hydroxyethyl)-3-(4-{4-[(1-methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)urea

MS (ESI) m/z 427.51.

Example 215 Preparation of1-(4-{4-[(1-methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea

MS (ESI) m/z 460.54.

Example 216 Preparation of1-(4-{4-[(1-methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]urea

MS (ESI) m/z 460.54.

Example 217 Preparation of1-(4-{4-[(1-methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-[4-(4-methylpiperazin-1-yl)phenyl]urea

MS (ESI) m/z 557.70.

Example 218 Preparation of1-{4-[(2,2-dimethylhydrazino)carbonyl]phenyl}-3-(4-{4-[(1-methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)urea

MS (ESI) m/z 545.65.

Example 219 Preparation of4-{[(4-{4-[(1-methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)carbamoyl]amino}-N-pyrrolidin-1-ylbenzamide

MS (ESI) m/z 571.69.

Example 220 Preparation of1-{4-[2-(dimethylamino)ethoxy]phenyl}-3-(4-{4-[(1-methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)urea

MS (ESI) m/z 546.68.

Example 221 Preparation of1-[4-(hydroxymethyl)phenyl]-3-(4-{4-[(1-methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)urea

MS (ESI) m/z 489.58

Example 222 Preparation of1-[4-(2-hydroxyethyl)phenyl]-3-(4-{4-[(1-methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)urea

MS (ESI) m/z 503.61.

Example 223 Preparation of1-{4-[4-(1-hydroxyethyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea

MS (ESI) m/z 421.46.

Example 224 Preparation of1-[4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-yl-1,3,5-triazin-2-yl)phenyl]-3-pyridin-4-ylurea

MS (ESI) m/z 514.59.

Example 225 Preparation of methyl4-({[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzoate

MS (ESI) m/z 462.51

Example 226 Preparation of methyl4-[({4-[4-(3,6-dihydro-2H-pyran-4-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzoate

MS (ESI) m/z 516.55.

Example 227 Preparation of4-[({4-[4-(3,6-dihydro-2H-pyran-4-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzoicacid

MS (ESI) m/z 502.53

Example 228 Preparation of1-(4-{4-morpholin-4-yl-6-[2-(pyridin-4-ylamino)ethyl]-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea

HRMS: calcd for C26H27N9O2+H+, 498.23605; found (ESI, [M+H]+Obs'd),498.2383.

Example 229 Preparation of1-[4-(4-methylpiperazin-1-yl)phenyl]-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea

HRMS: calcd for C31H39N9O3+H+, 586.32486; found (ESI, [M+H]+Obs'd),586.3245;

Example 230 Preparation of1-(4-acetylphenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea

HRMS: calcd for C28H31N7O4+H+, 530.25103; found (ESI, [M+H]+Obs'd),530.2508;

Example 231 Preparation of4-({[4-(4-butyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)-N-[2-(dimethylamino)ethyl]benzamide

MS (ESI) m/z 546.676.

Example 232 Preparation of1-[4-(4-butyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}urea

MS (ESI) m/z 559.4.

Example 233 Preparation of4-({[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzoicacid

MS (ESI) m/z 448.483

Example 234 Preparation of1-methyl-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)-1,3,5-triazin-2-yl]phenyl}urea

HRMS: calcd for C23H30N8O3+H+, 467.25136; found (ESI, [M+H]+Obs'd),467.2525.

Example 235 Preparation of1-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea

HRMS: calcd for C27H31N9O3+H+, 530.26226; found (ESI, [M+H]+Obs'd),530.2638;

Example 236 Preparation of1-[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}urea

MS (ESI) m/z 531.1.

Example 237 Preparation ofN-[2-(dimethylamino)ethyl]-4-({[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzamideExample 238 Preparation of1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea

MS (ESI) m/z 558.711

Example 239 Preparation of1-[4-(4-butyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(hydroxymethyl)phenyl]urea

MS (ESI) m/z 462.554.

Example 240 Preparation of4-[({4-[4-(3,6-dihydro-2H-pyran-4-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]-N-[2-(dimethylamino)ethyl]-N-methylbenzamide

MS (ESI) m/z 586.721.

Example 241 Preparation of1-[4-(4-butyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)urea

MS (ESI) m/z 586.741.

Example 242 Preparation ofN-[2-(dimethylamino)ethyl]-4-({[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)-N-methylbenzamide

MS (ESI) m/z 532.649.

Example 243 Preparation ofN-[2-(dimethylamino)ethyl]-4-({[4-(4-methoxy-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)-N-methylbenzamide

MS (ESI) m/z 534.62.

Example 244 Preparation ofN-[2-(dimethylamino)ethyl]-4-({[4-(4-methoxy-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzamide

MS (ESI) m/z 520.60.

Example 245 Preparation of4-({[4-(4-methoxy-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)-N-methyl-N-[2-(methylamino)ethyl]benzamide

MS (ESI) m/z 520.60.

Example 246 Preparation of1-[4-(4-methoxy-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}urea

MS (ESI) m/z 532.61.

Example 247 Preparation of1-{4-[(3,3-dimethylpiperazin-1-yl)carbonyl]phenyl}-3-[4-(4-methoxy-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea

MS (ESI) m/z 546.63.

Example 248 Preparation of4-({[4-(4-methoxy-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)-N-(2-piperidin-1-ylethyl)benzamide

MS (ESI) m/z 560.66.

Example 249 Preparation of1-(4-ethenylphenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea

MS (ESI) m/z 514.3; HRMS: calcd for C28H31N7O3+H+, 514.25611; found(ESI, [M+H]+Obs'd), 514.2561.

Example 250 Preparation of1-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea

HRMS: calcd for C32H₄₁N9O3+H+, 600.34051; found (ESI, [M+H]+Obs'd),600.3405.

Example 251 Preparation of4-({[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)-N-[4-(4-methylpiperazin-1-yl)phenyl]benzamide;MS (ESI) m/z 621.77. Example 252 Preparation of1-[4-(4-butyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-({[2-(dimethylamino)ethyl]amino}methyl)phenyl]urea;MS (ESI) m/z 532.71. Example 253 Preparation of4-({[4-(4-butyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)-N-[4-(4-methylpiperazin-1-yl)phenyl]benzamide;MS (ESI) m/z 649.82. Example 254 Preparation of1-[4-(4-butyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}urea;MS (ESI) m/z 544.728. Example 255 Preparation of1-[4-(4-butyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-(4-formylphenyl)urea;MS (ESI) m/z 461.2. Example 256 Preparation oftert-butyl(1R,4R)-5-(4-morpholin-4-yl-6-{4-[(pyridin-4-ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate;mp 192° C.; MS (ESI) m/z 574.3. Example 257 Preparation of tert-butyl(1R,4R)-5-[4-(4-{[(4-acetylphenyl)carbamoyl]amino}phenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate;mp 202° C.; MS (ESI) m/z 615.3; Example 258 Preparation of1-(4-{4-[(2-methoxyethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-3-ylurea;MS (ESI) m/z 476.54 Example 259 Preparation of1-{4-[4-{[(1S)-2-hydroxy-1-methylethyl]amino}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea;MS (ESI) m/z 476.54. Example 260 Preparation of1-{4-[4-{[(1R)-2-hydroxy-1-methylethyl]amino}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea

MS (ESI) m/z 476.54.

Example 261 Preparation of1-(4-{4-[(2-hydroxy-1,1-dimethylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-3-ylurea

MS (ESI) m/z 490.57.

Example 262 Preparation of1-{4-[4-(tert-butylamino)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea

MS (ESI) m/z 474.57.

Example 263 Preparation of4-({[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)-N-(pyridin-2-ylmethyl)benzamide;

mp 296-298° C.; MS (ESI) m/z 298.6. HRMS: calcd for C31H33N9O4+H+,596.27283; found (ESI, [M+H]+Obs'd), 596.2724; HRMS: calcd forC31H33N9O4+H+, 596.27283; found (ESI, [M+H]+ Calc'd), 596.2728.

Example 264 Preparation of1-[4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-yl-1,3,5-triazin-2-yl)phenyl]-3-(4-piperazin-1-ylphenyl)urea

HRMS: calcd for C32H39N9O3+H+, 598.32486; found (ESI, [M+H]+Obs'd),598.3247; HRMS: calcd for C32H39N9O3+H+, 598.32486; found (ESI, [M+H]+Calc'd), 598.3249;

Example 265 Preparation of1-[4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(4-methylpiperazin-1-yl)phenyl]urea

HRMS: calcd for C33H41N9O3+H+, 612.34051; found (ESI, [M+H]+Obs'd),612.3402;

Example 266 Preparation of1-{4-[2-(dimethylamino)ethoxy]phenyl}-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea

HRMS: calcd for C30H38N8O4+H+, 575.30888; found (ESI, [M+H]+Obs'd),575.3088; HRMS: calcd for C30H38N8O4+H+, 575.30888; found (ESI, [M+H]+Calc'd), 575.3089.

Example 267 Preparation of1-(4-{4-[2-(1,3-dioxan-2-yl)ethyl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea

HRMS: calcd for C25H29N7O4+H+, 492.23538; found (ESI, [M+H]+Obs'd),492.2364.

Example 268 Preparation of1-(4-{4-[2,5-bis(hydroxymethyl)pyrrolidin-1-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea

HRMS: calcd for C25H30N8O4+H+, 507.24628; found (ESI, [M+H]+Obs'd),507.2471.

Example 269 Preparation of4-({[4-(4-butyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)-N-{4-[2-(dimethylamino)ethoxy]phenyl}benzamide

MS (ESI) m/z 638.773.

Example 270 Preparation of1-{4-[(4-benzylpiperidin-1-yl)carbonyl]phenyl}-3-[4-(4-butyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea

MS (ESI) m/z 633.821.

Example 271 Preparation of4-({[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)-N-(1-methylpiperidin-4-yl)benzamide

MS (ESI) m/z 545.3.

Example 272 Preparation of4-({[4-(4-butyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)-N-(1-methylpiperidin-4-yl)benzamide

MS (ESI) m/z 573.4.

Example 273 Preparation of1-{4-[4-(6-hydroxy-3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea

MS (ESI) m/z 504.551.

Example 274 Preparation of1-(4-{4-[3-(dimethylamino)propyl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea

MS (ESI) m/z 462.56.

Example 275 Preparation of1-[4-(4-{3-[(1-methylethyl)amino]propyl}-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-pyridin-4-ylurea

MS (ESI) m/z 476.59.

Example 276 Preparation of1-{4-[4-morpholin-4-yl-6-(3-pyrrolidin-1-ylpropyl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea

MS (ESI) m/z 488.60.

Example 277 Preparation of1-(4-{4-[3-(4-methylpiperazin-1-yl)propyl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea

MS (ESI) m/z 517.64.

Example 278 Preparation of1-{4-[4-(3-{[2-(dimethylamino)ethyl]amino}propyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea

MS (ESI) m/z 505.63.

Example 279 Preparation of1-{4-[4-(3-hydroxypropyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea

MS (ESI) m/z 435.49.

Example 280 Preparation of1-{4-[4-morpholin-4-yl-6-(3-oxopropyl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea

MS (ESI) m/z 433.47.

Example 281 Preparation oftert-butyl-7-(4-morpholin-4-yl-6-{4-[(pyridin-4-ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate

HRMS: calcd for C30H37N9O5+H+, 604.29904; found (ESI, [M+H]+Obs'd),604.2993.

Example 282 Preparation of1-{4-[4-(6,8-dioxa-3-azabicyclo[3.2.1]oct-3-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea

HRMS: calcd for C24H26N8O4+H+, 491.21498; found (ESI, [M+H]+Obs'd),491.2155.

Example 283 Preparation of1-{4-[4-(3,6-dihydro-2H-pyran-4-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)urea

MS (ESI) m/z 612.759.

Example 284 Preparation of4-[({4-[4-(3,6-dihydro-2H-pyran-4-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]-N-[2-(dimethylamino)ethyl]benzamide

MS (ESI) m/z 572.694.

Example 285 Preparation of1-[4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-yl-1,3,5-triazin-2-yl)phenyl]-3-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}urea

MS (ESI) m/z 625.78

Example 286 Preparation ofN-[4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-yl-1,3,5-triazin-2-yl)phenyl]piperazine-1-carboxamide

MS (ESI) m/z 506.61

Example 287 Preparation of1-[4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(hydroxymethyl)phenyl]urea

MS (ESI) m/z 543.63.

Example 288 Preparation of1-[4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-yl-1,3,5-triazin-2-yl)phenyl]-3-{4-[(methylamino)methyl]phenyl}urea

MS (ESI) m/z 556.67.

Example 289 Preparation of1-{4-[2-(dimethylamino)ethoxy]phenyl}-3-[4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-yl-1,3,5-triazin-2-yl)phenyl]urea

MS (ESI) m/z 600.73.

Example 290 Preparation of1-{4-[4-morpholin-4-yl-6-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea

MS (ESI) m/z 503.57.

Example 291 Preparation of1-{4-[4-(7-methyl-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea

MS (ESI) m/z 517.60.

Example 292 Preparation of1-{4-[4-(7-acetyl-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea

MS (ESI) m/z 545.61.

Example 293 Preparation of1-(4-{4-[7-(methylsulfonyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea

MS (ESI) m/z 581.66.

Example 294 Preparation of1-[4-(4-methylpiperazin-1-yl)phenyl]-3-[4-(4-morpholin-4-yl-6-propyl-1,3,5-triazin-2-yl)phenyl]urea

MS (ESI) m/z 517.4.

Example 295 Preparation of1-{4-[2-(dimethylamino)ethoxy]phenyl}-3-[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea

MS (ESI) m/z 492.2.

Example 296 Preparation of1-[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(4-methylpiperazin-1-yl)phenyl]urea

MS (ESI) m/z 503.

Example 297 Preparation of1-[4-(4-methylpiperazin-1-yl)phenyl]-3-{4-[4-(2-methylpropyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}urea

MS (ESI) m/z 530.701.

Example 298 Preparation of1-{4-[(3,3-dimethylpiperazin-1-yl)carbonyl]phenyl}-3-[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea

MS (ESI) m/z 544.684.

Example 299 Preparation of4-({[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)-N-(1-methylazetidin-3-yl)benzamide

MS (ESI) m/z 517.3; MS (ESI) m/z 259.2.

Example 300 Preparation of methyl4-[({4-[4-(1-methylethyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzoate

mp 218° C.; MS (ESI) m/z 477.3.

Example 301 Preparation of4-[({4-[4-(1-methylethyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzoicacid

MS (ESI) m/z 463.3.

Example 302 Preparation oftert-butyl-(1R,4R)-5-{4-[4-({[4-(1-hydroxyethyl)phenyl]carbamoyl}amino)phenyl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

MS (ESI) m/z 617.4.

Example 303 Preparation of1-[4-(4-methylpiperazin-1-yl)phenyl]-3-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}urea

HRMS: calcd for C33H41N9O3+H+, 612.34051; found (ESI, [M+H]+Obs'd),612.3402; HRMS: calcd for C33H41N9O3+H+, 612.34051; found (ESI, [M+H]+Calc'd), 612.3405.

Example 304 Preparation of1-{4-[4-(1-methylethyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}urea

MS (ESI) m/z 544.66.

Example 305 Preparation ofN-[2-(dimethylamino)ethyl]-4-[({4-[4-(1-methylethyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide

MS (ESI) m/z 532.65.

Example 306 Preparation ofN-[2-(dimethylamino)ethyl]-N-methyl-4-[({4-[4-(1-methylethyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide

MS (ESI) m/z 546.68.

Example 307 Preparation ofN-(1-methylazetidin-3-yl)-4-[({4-[4-(1-methylethyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide

MS (ESI) m/z 530.63.

Example 308 Preparation of1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-{4-[4-(1-methylethyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}urea

MS (ESI) m/z 572.72.

Example 309 Preparation of4-[({4-[4-(1-methylethyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]-N-pyridin-4-ylbenzamide

MS (ESI) m/z 538.61.

Example 310 Preparation of4-[({4-[4-(1-methylethyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]-N-pyridin-3-ylbenzamide

MS (ESI) m/z 538.61.

Example 311 Preparation ofN-cyclobutyl-4-[({4-[4-(1-methylethyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide

MS (ESI) m/z 515.62.

Example 312 Preparation of1-{4-[4,6-di-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-1,3,5-triazin-2-yl]phenyl}-3-[4-(4-methylpiperazin-1-yl)phenyl]urea

MS (ESI) m/z 583.70.

Example 313 Preparation of1-{4-[4,6-di-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-1,3,5-triazin-2-yl]phenyl}-3-(4-piperazin-1-ylphenyl)urea

MS (ESI) m/z 569.67.

Example 314 Preparation of1-{4-[4,6-di-(1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-1,3,5-triazin-2-yl]phenyl}-3-[4-(4-methylpiperazin-1-yl)phenyl]urea

MS (ESI) m/z 583.70.

Example 315 Preparation of1-(2-fluoroethyl)-3-{4-[4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}urea

MS (ESI) m/z 561.6.

Example 316 Preparation of1-cyclopropyl-3-{4-[4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}urea

MS (ESI) m/z 555.71.

Example 317 Preparation of1-methyl-3-{4-[4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}urea

MS (ESI) m/z 529.67.

Example 318 Preparation of4-[({4-[4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide

MS (ESI) m/z 634.745.

Example 3191-{4-[4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-phenylurea

MS (ESI) m/z 591.72.

Example 320 Preparation of1-[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-{4-[(4-phenylpiperidin-1-yl)carbonyl]phenyl}urea

MS m/z 08-301429LMS.

Example 321 Preparation of4-({[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)-N-(pyridin-4-ylmethyl)benzamide

MS (ESI) m/z 539.4; MS (ESI) m/z 270.2.

Example 322 Preparation of1-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-3-{4-[4-(2-methylpropyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}urea

MS (ESI) m/z 558.711.

Example 323 Preparation of1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-{4-[4-(2-methylpropyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}urea

MS (ESI) m/z 586.765.

Example 324 Preparation ofN-[2-(dimethylamino)ethyl]-N-methyl-4-[({4-[4-(2-methylpropyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide

MS (ESI) m/z 560.727.

Example 325 Preparation of1-methyl-3-(4-{4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-[(4-piperazin-1-ylphenyl)amino]-1,3,5-triazin-2-yl}phenyl)urea

MS (ESI) m/z 515.62.

Example 326 Preparation of1-cyclopropyl-3-(4-{4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-[(4-piperazin-1-ylphenyl)amino]-1,3,5-triazin-2-yl}phenyl)urea

MS (ESI) m/z 541.66.

Example 327 Preparation of1-(2-fluoroethyl)-3-(4-{4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-[(4-piperazin-1-ylphenyl)amino]-1,3,5-triazin-2-yl}phenyl)urea

MS (ESI) m/z 547.64.

Example 328 Preparation of1-(2-hydroxyethyl)-3-(4-{4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-[(4-piperazin-1-ylphenyl)amino]-1,3,5-triazin-2-yl}phenyl)urea

MS (ESI) m/z 545.65.

Example 329 Preparation of4-{[(4-{4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-[(4-piperazin-1-ylphenyl)amino]-1,3,5-triazin-2-yl}phenyl)carbamoyl]amino}benzamide

MS (ESI) m/z 620.72.

Example 330 Preparation of1-(4-{4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-[(4-piperazin-1-ylphenyl)amino]-1,3,5-triazin-2-yl}phenyl)-3-phenylurea

MS (ESI) m/z 577.69.

Example 331 Preparation of1-methyl-3-{4-[4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}urea

MS (ESI) m/z 529.67.

Example 332 Preparation of1-cyclopropyl-3-{4-[4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}urea

MS (ESI) m/z 555.71.

Example 333 Preparation of1-(2-fluoroethyl)-3-{4-[4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}urea

MS (ESI) m/z 561.69.

Example 334 Preparation of4-[({4-[4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-yl]phenyl}carbamoyl)amino]benzamide

MS (ESI) m/z 634.745.

Example 335 Preparation of1-{4-[4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-phenylurea

MS (ESI) m/z 591.72;

Example 336 Preparation of1-(2,3′-bipyridin-4-yl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea

MS (ESI) m/z 566.4; HRMS: calcd for C30H31N9O3+H+, 566.26226; found(ESI, [M+H]+ Calc'd), 566.2623.

Example 337 Preparation of1-{4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}urea

MS (ESI) m/z 593.5.

Example 338 Preparation ofN-[2-(dimethylamino)ethyl]-N-methyl-4-[({4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide

MS (ESI) m/z 595.5.

Example 339 Preparation of1-{4-[4-(dimethylamino)piperidin-1-yl]phenyl}-3-{4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}urea

MS (ESI) m/z 593.4.

Example 340 Preparation of1-{4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea

MS (ESI) m/z 468.3.

Example 341 Preparation of1-{4-[4-(dimethylamino)piperidin-1-yl]phenyl}-3-[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea

MS (ESI) m/z 531.4.

Example 342 Preparation of4-[({4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzoicacid

MS (ESI) m/z 511.4.

Example 343 Preparation of1-{4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-[4-(4-methylpiperazin-1-yl)phenyl]urea

MS (ESI) m/z 565.4.

Example 344 Preparation of methyl4-[({4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzoate

MS (ESI) m/z 525.4.

Example 345 Preparation of1-{4-[4-(dimethylamino)piperidin-1-yl]phenyl}-3-[4-(4-morpholin-4-yl-6-phenyl-1,3,5-triazin-2-yl)phenyl]urea

MS (ESI) m/z 578.745.

Example 346 Preparation of1-[4-(4-morpholin-4-yl-6-phenyl-1,3,5-triazin-2-yl)phenyl]-3-pyridin-4-ylurea

MS (ESI) m/z 454.1.

Preparation of (2S,5R)-pyrrolidine-2,5-diyldimethanol hydrochloride

((2S,5R)-1-benzylpyrrolidine-2,5-diyl)dimethanol (2.2 g, 10 mmol) wasdissolved in ethanol/tetrahydrofuran (200 mL, 1:1), and the mixture wastreated with 10% palladium on carbon (250 mg). The suspension was shakenunder 50 psi of hydrogen until the consumption of hydrogen had ceased.The mixture was filtered through a pad of Celite™ diatomaceous earth,eluting with ethanol. The filtrate was concentrated to dryness toprovide the title compound as a golden oil that solidified uponprolonged storage. MS (ES⁺)=132.2 (M+H)⁺.

Preparation of((2S,5R)-1-(4-chloro-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)pyrrolidine-2,5-diyl)dimethanol

A suspension of 2,4-dichloro-6-(4-nitrophenyl)-1,3,5-triazine (2.2 g,8.0 mmol) in acetone (40 mL) was added to magnetically stirred ice water(60 mL). The mixture was treated with a solution of(2S,5R)-pyrrolidine-2,5-diyldimethanol hydrochloride (1.0 g, 6.0 mmol)in acetone/water (20 mL, 3:1), followed by a suspension of sodiumhydrogen carbonate (1.0 g, 12 mmol) in water (12 mL). After 30 minutesof stirring at 0° C., the mixture was treated with an additionalquantity of (2S,5R)-pyrrolidine-2,5-diyldimethanol hydrochloride (0.26g, 1.6 mmol) in water (3 mL), followed by sodium hydrogen carbonate(0.35 g) in water (5 mL). The suspension was allowed to stir overnightwhile regaining room temperature. The title compound was isolated byBüchner filtration, washed with water, and dried under house vacuum.Compound identification by mass spectrometry was achieved via theanalysis of the product reaction product of((2S,5R)-1-(4-chloro-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)pyrrolidine-2,5-diyl)dimethanolwith excess morpholine in ethanol. MS (ES⁺)=417.2 (M+morpholine−Cl)⁺.

Preparation of((2S,5R)-1-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)pyrrolidine-2,5-diyl)dimethanol

A suspension of((2S,5R)-1-(4-chloro-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)pyrrolidine-2,5-diyl)dimethanol(0.91 g, 2.5 mmol), 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (0.37g, 2.5 mmol) in ethanol (13 mL) was treated with triethylamine (1 mL)and heated in a microwave reactor for 20 minutes at 130° C. The reactionmixture was purified by automated flash chromatography(methanol/chloroform) to provide the title compound as a hard peachcolored foam. MS (ES⁺)=443.2 (M+H)⁺.

Preparation of8-(4-((2S,5R)-2,5-bis((tert-butyldimethylsilyloxy)methyl)pyrrolidin-1-yl)-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)-3-oxa-8-azabicyclo[3.2.1]octane

A solution of((2S,5R)-1-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)pyrrolidine-2,5-diyl)dimethanol(approximately 2.7 mmol) in dichloromethane (15 mL) was treatedsuccessively with tert-butyl dimethyl chlorosilane (1.0 g, 6.8 mmol) andimidazole (0.55 g, 8.1 mmol). The resulting suspension was stirredovernight at room temperature and then quenched with water. The aqueousphase was extracted three times with dichloromethane. The combinedextracts were dried over anhydrous magnesium sulfate, filtered, andconcentrated to dryness under reduced pressure. The crude residue waspurified by automated flash chromatography (hexanes/ethyl acetate) toprovide the title material. MS (ES⁺)=671.4 (M+H)⁺.

Preparation of4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2S,5R)-2,5-bis((tert-butyldimethylsilyloxy)methyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)aniline

A suspension of palladium on charcoal (10%, 50 mg) and8-(4-((2S,5R)-2,5-bis((tert-butyldimethylsilyloxy)methyl)pyrrolidin-1-yl)-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)-3-oxa-8-azabicyclo[3.2.1]octane(0.55 g, 1.2 mmol) in tetrahydrofuran (20 mL) was stirred under aballoon of hydrogen overnight. The mixture was filtered through a pad ofCelite™ diatomaceous earth and concentrated under reduced pressure toprovide the title compound as a tan foam (0.42 g, 80%).

MS (ES⁺)=642.4 (M+H)⁺.

Example 347 Preparation of1-(4-{4-[(2R,5S)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea

A solution of4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2S,5R)-2,5-bis((tert-butyldimethylsilyloxy)methyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)aniline(0.16 mmol) in dichloromethane (4 mL) was treated successively withtriethylamine (1.6 mmol, 210 μL) and a triphosgene (24 mg, 0.08 mmol)solution in dichloromethane (500 μL). After 5 minutes, the mixture wastreated with a solution of 4-aminopyridine (45 mg, 0.48 mmol) in warmtetrahydrofuran. After 1 hour, the reaction mixture was quenched withmethanol and concentrated to dryness. The crude residue was treated witha saturated solution of hydrogen chloride in methanol. Upon completedesilylation, the mixture was concentrated to dryness and the residuepurified by reverse-phase high performance liquid chromatography using aPhenomenex Prodigy column running a gradient elution of 5%acetonitrile/95% of 0.1% aqueous trifluoroacetic acid to 50%acetonitrile over 25 minutes. After concentration, the title compoundwas obtained as it trifluoroacetic acid salt (132 mg). MS (ES⁺)=533.3(M+H)⁺.

Example 348 Preparation of1-(4-{4-[(2R,5S)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl}phenyl)-3-[4-(4-methylpiperazin-1-yl)phenyl]urea

A solution of4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2S,5R)-2,5-bis((tert-butyldimethylsilyloxy)methyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)aniline(0.16 mmol) in dichloromethane (4 mL) was treated successively withtriethylamine (1.6 mmol, 210 μL) and a triphosgene (24 mg, 0.08 mmol)solution in dichloromethane (500 μL). After 5 minutes, the mixture wastreated with 4-(4-methylpiperazin-1-yl)aniline (61 mg, 0.32 mmol). After1 hour, the reaction mixture was quenched with methanol and concentratedto dryness. The crude residue was treated with a saturated solution ofhydrogen chloride in methanol. Upon complete desilylation, the mixturewas concentrated to dryness and the residue purified by reverse-phasehigh performance liquid chromatography using a Phenomenex Prodigy columnrunning a gradient elution of 5% acetonitrile/95% of 0.1% aqueoustrifluoroacetic acid to 50% acetonitrile over 25 minutes. Afterconcentration, the title compound was obtained as it trifluoroaceticacid salt (100 mg). MS (ES⁺)=630.4 (M+H)⁺.

Example 349 Preparation of1-(6-chloropyridin-3-yl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea

HRMS: calcd for C25H27ClN8O3+H+, 523.19674; found (ESI, [M+H]+Obs'd),523.1975.

Example 350 Preparation of1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl]phenyl}urea

MS (ESI) m/z 614.8

Example 351 Preparation of1-(4-aminophenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea

MS (ESI) m/z 477.1.

Example 352 Preparation ofN-[4-({[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)phenyl]-N2,N2-dimethylglycinnamide

The4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-yl-1,3,5-triazin-2-yl)aniline(50 mg, 0.127 mmol) was dissolved in dichloromethane (1.5 mL) andtriethylamine (0.120 mL) and added to a solution of triphosgene (17 mg)in dichloromethane (0.5 mL). Stir for 5 minutes then addedN-(4-aminophenyl)-N2,N2-dimethylglycinnamide (27 mg, 0.14 mmol).Purified by Gilson HPLC to provide the title compound as the TFA salt:31.8 mg (35%) (M+H) m/z 614.3.

Example 353 Preparation ofN-[4-({[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)phenyl]-2-pyrrolidin-1-ylacetamide

The4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-yl-1,3,5-triazin-2-yl)aniline(50 mg, 0.127 mmol) was dissolved in dichloromethane (1.5 mL) andtriethylamine (0.120 mL) and added to a solution of triphosgene (17 mg)in dichloromethane (0.5 mL). Stir for 5 minutes then addedN-(4-aminophenyl)-2-pyrrolidin-1-ylacetamide (30 mg, 0.14 mmol) Purifiedby Gilson HPLC to provide the title compound as the TFA salt: 63.1 mg(66%) (M+H) m/z 640.3.

Example 354 Preparation of1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(piperazin-1-yl)phenylamino)-1,3,5-triazin-2-yl)phenyl)-3-methylurea

Prepared as shown in Scheme 1, using commercially available tert-butyl4-(4-aminophenyl)piperazine-1-carboxylate in the second nucleophilicaromatic substitution step. Following urea formation using methylamine,the Boc-piperazine intermediate was treated with TFA to provide thetitle compound. (M+H) 516.3.

Example 355 Preparation of1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(piperazin-1-yl)phenylamino)-1,3,5-triazin-2-yl)phenyl)-3-cyclopropylurea

Prepared as shown in Scheme 1, using commercially available tert-butyl4-(4-aminophenyl)piperazine-1-carboxylate in the second nucleophilicaromatic substitution step. Following urea formation usingcyclopropylamine, the Boc-piperazine intermediate was treated with TFAto provide the title compound. (M+H) 542.3.

Example 356 Preparation of1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(piperazin-1-yl)phenylamino)-1,3,5-triazin-2-yl)phenyl)-3-(2-fluoroethyl)urea

Prepared as shown in Scheme 1, using commercially available tert-butyl4-(4-aminophenyl)piperazine-1-carboxylate in the second nucleophilicaromatic substitution step. Following urea formation using2-fluoroethylamine, the Boc-piperazine intermediate was treated with TFAto provide the title compound. (M+H) 548.3.

Example 357 Preparation of1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(piperazin-1-yl)phenylamino)-1,3,5-triazin-2-yl)phenyl)-3-(2-hydroxyethyl)urea

Prepared as shown in Scheme 1, using commercially available tert-butyl4-(4-aminophenyl)piperazine-1-carboxylate in the second nucleophilicaromatic substitution step. Following urea formation using2-aminoethanol, the Boc-piperazine intermediate was treated with TFA toprovide the title compound. (M+H) 546.3.

Example 358 Preparation of4-(3-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(piperazin-1-yl)phenylamino)-1,3,5-triazin-2-yl)phenyl)ureido)benzamide

Prepared as shown in Scheme 1, using commercially available tert-butyl4-(4-aminophenyl)piperazine-1-carboxylate in the second nucleophilicaromatic substitution step. Following urea formation using4-aminobenzamide, the Boc-piperazine intermediate was treated with TFAto provide the title compound. (M+H) 621.3.

Example 359 Preparation of1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(piperazin-1-yl)phenylamino)-1,3,5-triazin-2-yl)phenyl)-3-phenylurea

Prepared as shown in Scheme 1, using commercially available tert-butyl4-(4-aminophenyl)piperazine-1-carboxylate in the second nucleophilicaromatic substitution step. Following urea formation using aniline, theBoc-piperazine intermediate was treated with TFA to provide the titlecompound. (M+H) 578.3.

Example 360 Preparation of1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(piperidin-4-ylamino)-1,3,5-triazin-2-yl)phenyl)-3-ethylurea

Prepared as shown in Scheme 1, using commercially available tert-butyl4-aminopiperidine-1-carboxylate in the second nucleophilic aromaticsubstitution step. Following urea formation using ethylamine, theBoc-piperidine intermediate was treated with TFA to provide the titlecompound. (M+H) 453.6.

Example 361 Preparation of1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(piperidin-4-ylamino)-1,3,5-triazin-2-yl)phenyl)-3-ethylurea

Prepared as shown in Scheme 1, usingN1-(2-(dimethylamino)ethyl)-N-1-methylbenzene-1,4-diamine in the ureaformation step. (M+H) 614.3.

The required benzene-1,4-diamine intermediates for the followingcompounds were prepared as outlined in Scheme 4.

Example 362 Preparation of1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(piperidin-4-ylamino)-1,3,5-triazin-2-yl)phenyl)-3-ethylurea

Prepared as shown in Scheme 1, using1-(4-aminophenyl)-N,N-dimethylpiperidin-4-amine in the urea formationstep. (M+H) 640.4.

Preparation of 1-(4-aminophenyl)-N,N-dimethylpiperidin-4-amine

Prepared from 4-fluoronitrobenzene and the appropriate amine as shown inScheme 4.

Example 363 Preparation of1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(piperidin-4-ylamino)-1,3,5-triazin-2-yl)phenyl)-3-ethylurea

Prepared as shown in Scheme 1, usingN1-(2-methoxyethyl)benzene-1,4-diamine in the urea formation step. (M+H)587.3.

Preparation of N1-(2-methoxyethyl)benzene-1,4-diamine

Prepared from 4-fluoronitrobenzene and the appropriate amine as shown inScheme 4.

Example 364 Preparation of1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(piperidin-4-ylamino)-1,3,5-triazin-2-yl)phenyl)-3-ethylurea

Prepared as shown in Scheme 1, using 2-(4-aminophenylamino)ethanol inthe urea formation step. (M+H) 573.3.

Preparation of 2-(4-aminophenylamino)ethanol

Prepared from 4-fluoronitrobenzene and the appropriate amine as shown inScheme 4.

Example 365 Preparation of1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(piperidin-4-ylamino)-1,3,5-triazin-2-yl)phenyl)-3-ethylurea

Prepared as shown in Scheme 1, usingN1-(1-methylpiperidin-4-yl)benzene-1,4-diamine in the urea formationstep. (M+H) 626.3.

Preparation of N1-(1-methylpiperidin-4-yl)benzene-1,4-diamine

Prepared from 4-fluoronitrobenzene and the appropriate amine as shown inScheme 4.

Example 366 Preparation of1-(4-(4,6-di(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(piperazin-1-ylmethyl)phenyl)urea

Prepared as shown in Scheme 1, using commercially available tert-butyl4-(4-aminobenzyl)piperazine-1-carboxylate in the urea formation step.Following urea formation, the Boc-piperidine intermediate was treatedwith TFA to provide the title compound. (M+H) 612.3.

Example 367 Preparation of1-(4-(4,6-di(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-((dimethylamino)methyl)phenyl)urea

Prepared as shown in Scheme 1, using commercially available4-((dimethylamino)methyl)aniline in the urea formation step. (M+H)571.3.

Example 368 Preparation of1-(4-(aminomethyl)phenyl)-3-(4-(4,6-di(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)urea

Prepared as shown in Scheme 1, using commercially available tert-butyl4-aminobenzylcarbamate in the urea formation step. Following ureaformation, the Boc-amine intermediate was treated with TFA to providethe title compound. (M+H) 543.3.

Example 369 Preparation of1-(4-(4,6-di(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(pyrrolidin-1-ylmethyl)phenyl)urea

Prepared as shown in Scheme 1, using commercially available4-(pyrrolidin-1-ylmethyl)aniline in the urea formation step. (M+H)597.3.

Example 370 Preparation of1-(4-(4,6-di(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)urea

Prepared as shown in Scheme 1, using4-(2-(4-methylpiperazin-1-yl)ethoxy)aniline in the urea formation step.(M+H) 656.4.

The required 4-(alkoxy)aniline intermediates for the following compoundswere prepared as outlined in Scheme 5.

Example 371 Preparation of1-(4-(4,6-di(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)urea

Prepared as shown in Scheme 1, using4-(2-(pyrrolidin-1-yl)ethoxy)aniline in the urea formation step. (M+H)627.3.

Preparation of 4-(2-(pyrrolidin-1-yl)ethoxy)aniline

Prepared from 4-fluoronitrobenzene and the appropriate alcohol as shownin Scheme 5.

Example 372 Preparation of1-(4-(4,6-di(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-hydroxyethoxy)phenyl)urea

Prepared as shown in Scheme 1, using 2-(4-aminophenoxy)ethanol in theurea formation step. (M+H) 574.3.

Preparation of 2-(4-aminophenoxy)ethanol

Prepared from 4-fluoronitrobenzene and the appropriate alcohol as shownin Scheme 5.

Example 373 Preparation ofN-(4-(3-(4-(4,6-di(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)ureido)phenyl)-2-(dimethylamino)acetamide

Prepared as shown in Scheme 1, using commercially availableN-(4-aminophenyl)-2-(dimethylamino)acetamide in the urea formation step.(M+H) 614.3.

Example 374 Preparation ofN-(4-(3-(4-(4,6-di(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)ureido)phenyl)-2-(4-methylpiperazin-1-yl)acetamide

Prepared as shown in Scheme 1, using commercially availableN-(4-aminophenyl)-2-(4-methylpiperazin-1-yl)acetamide in the ureaformation step. (M+H) 669.4.

Example 375 Preparation ofN-(4-(3-(4-(4,6-di(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)ureido)phenyl)-2-(pyrrolidin-1-yl)acetamide

Prepared as shown in Scheme 1, using commercially availableN-(4-aminophenyl)-2-(pyrrolidin-1-yl)acetamide in the urea formationstep. (M+H) 640.3.

Example 376 Preparation of1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-3-yl)urea

Prepared as shown in Scheme 1, using commercially availablepyridin-3-amine in the urea formation step. (M+H) 461.2.

Example 377 Preparation of1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea

Prepared as shown in Scheme 1, using commercially availablepyridin-4-amine in the urea formation step. (M+H) 461.2.

Example 378 Preparation of1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea

Prepared as shown in Scheme 1, using commercially available4-(4-methylpiperazin-1-yl)aniline in the urea formation step. (M+H)558.3.

Example 379 Preparation of1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-triazin-2-yl)phenyl)-3-(4-((4-methylpiperazin-1-yl)methyl)phenyl)urea

Prepared as shown in Scheme 1, using commercially available4-((4-methylpiperazin-1-yl)methyl)aniline in the urea formation step.(M+H) 572.3.

Example 380 Preparation of1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(piperazin-1-ylmethyl)phenyl)urea

Prepared as shown in Scheme 1, using commercially available tert-butyl4-(4-aminobenzyl)piperazine-1-carboxylate in the urea formation step.Following urea formation, the Boc-piperazine intermediate was treatedwith TFA to provide the title compound. (M+H) 558.3.

Example 381 Preparation of1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-triazin-2-yl)phenyl)-3-(4-((dimethylamino)methyl)phenyl)urea

Prepared as shown in Scheme 1, using commercially available4-((dimethylamino)methyl)aniline in the urea formation step. (M+H)517.3.

Example 382 Preparation of1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(aminomethyl)phenyl)urea

Prepared as shown in Scheme 1, using commercially available tert-butyl4-aminobenzylcarbamate in the urea formation step. Following ureaformation, the Boc-amine intermediate was treated with TFA to providethe title compound. (M+H) 489.3.

Example 383 Preparation of1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(pyrrolidin-1-ylmethyl)phenyl)urea

Prepared as shown in Scheme 1, using commercially available4-(pyrrolidin-1-ylmethyl)aniline in the urea formation step. (M+H)543.3.

Example 384 Preparation of1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)urea

Prepared as shown in Scheme 1, using4-(2-(pyrrolidin-1-yl)ethoxy)aniline in the urea formation step. (M+H)573.3.

Example 385 Preparation of1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-(dimethylamino)ethoxy)phenyl)urea

Prepared as shown in Scheme 1, using 4-(2-(dimethylamino)ethoxy)anilinein the urea formation step. (M+H) 547.3.

Preparation of 4-(2-(dimethylamino)ethoxy)aniline

Prepared from 4-fluoronitrobenzene and the appropriate alcohol as shownin Scheme 5.

Example 386 Preparation of1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-triazin-2-yl)phenyl)-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)urea

Prepared as shown in Scheme 1, using commercially available5-(4-methylpiperazin-1-yl)pyridin-2-amine in the urea formation step.(M+H) 559.3.

Example 387 Preparation of1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(piperazin-1-yl)phenyl)urea

Prepared as shown in Scheme 1, using commercially available tert-butyl4-(4-aminophenyl)piperazine-1-carboxylate in the urea formation step.Following urea formation, the Boc-amine intermediate was treated withTFA to provide the title compound. (M+H) 544.3.

Example 388 Preparation of1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(dimethylamino)piperidin-1-yl)phenyl)urea

Prepared as shown in Scheme 1, using1-(4-aminophenyl)-N,N-dimethylpiperidin-4-amine in the urea formationstep. (M+H) 586.4.

Example 389 Preparation of1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropyl(methyl)amino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea

Prepared as shown in Scheme 1, using commercially available4-(4-methylpiperazin-1-yl)aniline in the urea formation step. (M+H)572.3.

Example 390 Preparation of1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropyl(methyl)amino)-1,3,5-triazin-2-yl)phenyl)-3-(4-((dimethylamino)methyl)phenyl)urea

Prepared as shown in Scheme 1, using commercially available4-((dimethylamino)methyl)aniline in the urea formation step. (M+H)531.3.

Example 391 Preparation of1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropyl(methyl)amino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-(dimethylamino)ethoxy)phenyl)urea

Prepared as shown in Scheme 1, using 4-(2-(dimethylamino)ethoxy)anilinein the urea formation step. (M+H) 561.3.

Example 392 Preparation of1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-thiomorpholino-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-3-yl)urea(Scheme 6) Step 1: Preparation of8-(4-chloro-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)-3-oxa-8-azabicyclo[3.2.1]octane

A solution of 2,4-dichloro-6-(4-nitrophenyl)-1,3,5-triazine (1.25 g,4.61 mmol) in acetone (20 mL) and ice water (20 mL) was prepared. Tothis was added dropwise over 10 minutes a suspension of3-oxa-8-azabicyclo[3.2.1]octane-hydrochloride (0.655 g, 4.38 mmol) andsodium bicarbonate (0.775 g, 9.22 mmol) in acetone (15 mL) and water (15mL). The resulting tan solution was allowed to stir at 0° C. for 2hours, then gradually allowed to warm to room temperature over 18 hours.The light brown suspension was filtered and washed with water. The crudeproduct was purified by silica gel column chromatography, eluting with0-1.5% methanol in methylene chloride to provide8-(4-chloro-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)-3-oxa-8-azabicyclo[3.2.1]octane(0.89 g, 56%) as an off-white solid. (M+H) 348.1.

Step 2: Preparation of8-(4-(4-nitrophenyl)-6-thiomorpholino-1,3,5-triazin-2-yl)-3-oxa-8-azabicyclo[3.2.1]octane

A solution of8-(4-chloro-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)-3-oxa-8-azabicyclo[3.2.1]octane(0.450 g, 1.29 mmol) in acetone (5 mL) and water (10 mL) was prepared.To this was added sodium carbonate (0.274 g, 2.59 mmoles), followed bythiomorpholine (0.134 ml, 1.42 mmol). The resulting light tan suspensionwas allowed to stir at 60° C. for 2.5 hours. The suspension was filteredand the solid was washed with water and dried in vacuo to provide8-(4-(4-nitrophenyl)-6-thiomorpholino-1,3,5-triazin-2-yl)-3-oxa-8-azabicyclo[3.2.1]octane(0.455 g, 85%) as a white solid. HRMS 415.1546 (M+H, calc.), 415.1526(M+H, obs.).

Step 3: Preparation of4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-thiomorpholino-1,3,5-triazin-2-yl)aniline

A suspension of8-(4-(4-nitrophenyl)-6-thiomorpholino-1,3,5-triazin-2-yl)-3-oxa-8-azabicyclo[3.2.1]octane(0.418 g, 1.01 mmol) in pyridine (3 ml) and DMF (6 ml) was prepared.Tin(II) chloride dihydrate (0.569 g, 2.52 mmol) was then added and theoff-white suspension was allowed to stir at room temperature for 16hours, at which time the suspension was light yellow. The suspension wasfiltered, washing with methanol, and concentrated. LCMS indicatedreaction had not gone to completion. The crude product was dissolved inDMF (6 ml) and pyridine (3 ml) and additional tin(II) chloride dihydrate(0.569 g, 2.52 mmol) was added. The solution was allowed to stir at roomtemperature for 18 hours, then filtered. The precipitate was washed withmethanol and the filtrate was concentrated to provide4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-thiomorpholino-1,3,5-triazin-2-yl)aniline(0.195 g, 50%) as a yellow solid. (M+H) 385.1.

Step 4: Preparation of1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-thiomorpholino-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-3-yl)urea

The method of urea formation using triphosgene and triethylamine inmethylene chloride, described in Scheme 1, was utilized usingcommercially available pyridin-3-amine as the amine component.Purification by HPLC (5-95% acetonitrile in water over 20 minutes, 0.05%TFA buffer, Waters Atlantis column) provided1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-thiomorpholino-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-3-yl)urea(0.032 g, 63%) as an off-white solid. (M+H) 505.2.

Example 393 Preparation of1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-thiomorpholino-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea

Prepared as shown in Scheme 6, using commercially availablepyridin-4-amine in the urea formation step. Yield; 28 mg (54%); (M+H)505.2.

Example 394 Preparation of1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-thiomorpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea

Prepared as shown in Scheme 6, using commercially available4-(4-methylpiperazin-1-yl)aniline in the urea formation step. Yield; 44mg (73%); (M+H) 602.3.

Example 395 Preparation of1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-thiomorpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-((dimethylamino)methyl)phenyl)urea

Prepared as shown in Scheme 6, using commercially available4-((dimethylamino)methyl)aniline in the urea formation step. Yield; 19mg (34%); (M+H) 561.3.

Example 365 Preparation of1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-thiomorpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-(dimethylamino)ethoxy)phenyl)urea

Prepared as shown in Scheme 6, using 4-(2-(dimethylamino)ethoxy)anilinein the urea formation step. Yield; 35 mg (59%); (M+H) 591.3.

Example 397 Preparation of1-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea

Prepared as shown in Scheme 1, using commercially availablepyridin-4-amine in the urea formation step. Yield; 44 mg (75%); (M+H)491.2.

Example 398 Preparation of1-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-3-yl)urea

Prepared as shown in Scheme 1, using commercially availablepyridin-3-amine in the urea formation step. Yield; 46 mg (79%); (M+H)491.2.

Example 399 Preparation of1-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea

Prepared as shown in Scheme 1, using commercially available4-((dimethylamino)methyl)aniline in the urea formation step. Yield; 57mg (81%); (M+H) 588.3.

Example 400 Preparation of1-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)urea

Prepared as shown in Scheme 1, using commercially available5-(4-methylpiperazin-1-yl)pyridin-2-amine in the urea formation step.Yield; 56 mg (79%); (M+H) 589.3.

Example 401 Preparation of1-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-((dimethylamino)methyl)phenyl)urea

Prepared as shown in Scheme 1, using commercially available4-((dimethylamino)methyl)aniline in the urea formation step. Yield; 28mg (43%); (M+H) 547.3.

Example 402 Preparation of1-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-(dimethylamino)ethoxy)phenyl)urea

Prepared as shown in Scheme 1, using 4-(2-(dimethylamino)ethoxy)anilinein the urea formation step. Yield; 50 mg (72%); (M+H) 577.3.

Example 403 Preparation of1-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)urea

Prepared as shown in Scheme 1, using4-(2-(pyrrolidin-1-yl)ethoxy)aniline in the urea formation step. Yield;41 mg (57%); (M+H) 603.3.

Example 404 Preparation of1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(3,6-dihydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea(Scheme 7) Step 1: Preparation of8-(4-chloro-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)-3-oxa-8-azabicyclo[3.2.1]octane:Prepared as shown in Scheme 6, described in Example 392, Step 1. Step 2:Preparation of8-(4-(3,6-dihydro-2H-pyran-4-yl)-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)-3-oxa-8-azabicyclo[3.2.1]octane

A microwave vial was charged with8-(4-chloro-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)-3-oxa-8-azabicyclo[3.2.1]octane(0.440 g, 1.27 mmoles). Toluene (6 mL) was then added and the solutionwas sparged with nitrogen for 10 minutes.Tetrakis(triphenylphosphine)palladium(0) (0.088 g, 0.076 mmol) andtributyl(3,6-dihydro-2H-pyran-4-yl)stannane (0.567 g, 1.52 mmol) wereadded. The vial was sealed and heated to 100° C. for 40 minutes viamicrowave. Additional tributyl(3,6-dihydro-2H-pyran-4-yl)stannane (0.283g, 0.76 mmoles) and tetrakis(triphenylphosphine)palladium(0) (0.022 g,0.019 mmol) were added and the suspension was heated to 110° C. bymicrowave for additional 90 minutes. The suspension was then cooled toroom temperature and filtered through Celite™. The filter cake waswashed with ethyl acetate and the filtrate was concentrated underreduced pressure. The crude product was purified by silica gelchromatography, eluting with 0-2% methanol in methylene chloride, toprovide8-(4-(3,6-dihydro-2H-pyran-4-yl)-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)-3-oxa-8-azabicyclo[3.2.1]octane(0.430 g, 86%) as a light yellow solid. HRMS 396.1666 (M+H, calc.),396.1668 (M+H, obs.).

Step 3: Preparation of4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(3,6-dihydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)aniline

A mixture of iron powder (0.071 g, 1.27 mmoles) in acetic acid (2 ml)was heated to 55° C. for 15 minutes. Water (2 ml) was then added and oilbath was turned off. A solution of8-(4-(3,6-dihydro-2H-pyran-4-yl)-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)-3-oxa-8-azabicyclo[3.2.1]octane(0.100 g, 0.253 mmol) in ethyl acetate (2 ml) was then added to thiswarm solution over 5 minutes. The mixture was cooled to RT and allowedto stir for 16 hours. The mixture was extracted with ethyl acetate bydecantation (4×) into a sep. funnel containing saturated aqueous sodiumcarbonate. The combined organic extracts were washed with water, brine,dried, and concentrated to provide4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(3,6-dihydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)aniline(0.068 g, 74%), which was used in the next step without purification.(M+H) 366.4.

Step 4: Preparation of1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(3,6-dihydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea

The method of urea formation using triphosgene and triethylamine inmethylene chloride, described in Scheme 1, was utilized usingcommercially available pyridin-4-amine as the amine component.Purification by HPLC (5-95% acetonitrile in water over 20 minutes, 0.05%TFA buffer, Waters Atlantis column) provided1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(3,6-dihydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea(0.034 g, 75%) as a light yellow solid. (M+H) 486.2.

Example 405 Preparation of1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(3,6-dihydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea

Prepared as shown in Scheme 7, using commercially available4-(4-methylpiperazin-1-yl)aniline in the urea formation step. Yield; 44mg (82%); (M+H) 583.3.

Example 406 Preparation of1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea

Prepared as shown in Scheme 7; representative synthesis described below.

Preparation of4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)aniline

A solution of8-(4-(3,6-dihydro-2H-pyran-4-yl)-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)-3-oxa-8-azabicyclo[3.2.1]octane(prepared as described in Example DJR-51, Step 2) (0.260 g, 0.658 mmol)in ethyl acetate (5 ml), methanol (5 ml), and methylene chloride (2ml—added due to poor solubility of SM in EA/methanol) was prepared and10% palladium on carbon (0.078 g, 30% by weight) was added. The flaskwas purged with hydrogen gas (balloon) and allowed to stir underpositive pressure of hydrogen for 16 hours. Additional palladium oncarbon (0.039 g) was added and the suspension was purged with hydrogengas (balloon) and stirred for an additional 3 hours. The flask waspurged with hydrogen gas and stirred for an additional 1 hour. Thesuspension was filtered through Celite™, the filter cake was washed withethyl acetate, and the filtrate was concentrated to provide4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)aniline(0.220 g, 91%) as an off-white solid. HRMS 368.2080 (M+H, calc.),368.2085 (M+H, obs.).

Preparation of1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea

The method of urea formation using triphosgene and triethylamine inmethylene chloride, described in Scheme 1, was utilized usingcommercially available pyridin-4-amine as the amine component.Purification by HPLC (5-95% acetonitrile in water over 20 minutes, 0.05%TFA buffer, Waters Atlantis column) provided1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea(0.0461 g, 82%) as an off-white solid. (M+H) 488.2.

Example 407 Preparation of1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea

Prepared as shown in Scheme 7, using commercially available4-(4-methylpiperazin-1-yl)aniline in the urea formation step. Yield; 54mg (79%); (M+H) 585.3.

Example 408 Preparation of1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-(dimethylamino)ethoxy)phenyl)urea

Prepared as shown in Scheme 7, using 4-(2-(dimethylamino)ethoxy)anilinein the urea formation step. Yield; 49 mg (73%); (M+H) 572.3.

Example 409 Preparation of1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-((dimethylamino)methyl)phenyl)urea

Prepared as shown in Scheme 7, using commercially available4-((dimethylamino)methyl)aniline in the urea formation step. Yield; 21mg (33%); (M+H) 544.3.

Example 410 Preparation of1-(4-(4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea

Prepared as shown in Scheme 1, using commercially availablepyridin-4-amine in the urea formation step. Yield; 45 mg (70%); (M+H)489.2.

Example 411 Preparation of1-(4-(4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-3-yl)urea

Prepared as shown in Scheme 1, using commercially availablepyridin-3-amine in the urea formation step. Yield; 60 mg (95%); (M+H)489.2.

Example 412 Preparation of1-(4-(4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea

Prepared as shown in Scheme 1, using commercially available4-(4-methylpiperazin-1-yl)aniline in the urea formation step. Yield; 69mg (90%); (M+H) 586.3.

Example 413 Preparation of1-(4-(4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-((4-methylpiperazin-1-yl)methyl)phenyl)urea

Prepared as shown in Scheme 1, using commercially available4-((4-methylpiperazin-1-yl)methyl)aniline in the urea formation step.Yield; 73 mg (94%); (M+H) 600.3.

Example 414 Preparation of1-(4-(4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(pyrrolidin-1-ylmethyl)phenyl)urea

Prepared as shown in Scheme 1, using commercially available4-(pyrrolidin-1-ylmethyl)aniline in the urea formation step. Yield; 56mg (75%); (M+H) 571.3.

Example 415 Preparation of1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-3-yl)urea

Prepared as shown in Scheme 1, using commercially availablepyridin-3-amine in the urea formation step. Yield; 44 mg (66%); (M+H)503.2.

Example 416 Preparation of1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea

Prepared as shown in Scheme 1, using commercially availablepyridin-4-amine in the urea formation step. Yield; 35 mg (53%); (M+H)503.2.

Example 417 Preparation of1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea

Prepared as shown in Scheme 1, using commercially available4-(4-methylpiperazin-1-yl)aniline in the urea formation step. Yield; 58mg (62%); (M+H) 600.3.

Example 418 Preparation of1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(pyrrolidin-1-ylmethyl)phenyl)urea

Prepared as shown in Scheme 1, using commercially available4-(pyrrolidin-1-ylmethyl)aniline in the urea formation step. Yield; 41mg (45%); (M+H) 585.5.

Example 419 Preparation of1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-(dimethylamino)ethoxy)phenyl)urea

Prepared as shown in Scheme 1, using 4-(2-(dimethylamino)ethoxy)anilinein the urea formation step. Yield; 43 mg (47%); (M+H) 589.3.

Example 420 Preparation of(R)-1-(4-(4-(3-methylmorpholino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-3-yl)urea

Prepared as shown in Scheme 7, using commercially availablepyridin-3-amine in the urea formation step. Yield; 45 mg (77%); (M+H)476.2.

Example 421 Preparation of(R)-1-(4-(4-(3-methylmorpholino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea

Prepared as shown in Scheme 7, using commercially available4-(4-methylpiperazin-1-yl)aniline in the urea formation step. Yield; 53mg (75%); (M+H) 573.3.

Example 422 Preparation of(R)-1-(4-(4-(3-methylmorpholino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(piperazin-1-yl)phenyl)urea

Prepared as shown in Scheme 7, using commercially available tert-butyl4-(4-aminophenyl)piperazine-1-carboxylate in the urea formation step.Following urea formation, the Boc-piperazine intermediate was treatedwith TFA to provide the title compound. Yield; 63 mg (90%); (M+H) 559.3.

Example 423 Preparation of1-(4-(4-((R)-3-methylmorpholino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-((S)-3-methylpiperazin-1-yl)phenyl)urea

Prepared as shown in Scheme 7, using (S)-tert-butyl4-(4-aminophenyl)-3-methylpiperazine-1-carboxylate in the urea formationstep. Following urea formation, the Boc-piperazine intermediate wastreated with TFA to provide the title compound. Yield; 60 mg (71%);(M+H) 573.3.

Preparation of (S)-tert-butyl4-(4-aminophenyl)-3-methylpiperazine-1-carboxylate

Prepared from 4-fluoronitrobenzene and the appropriate amine as shown inScheme 4.

Example 424 Preparation of1-(4-(4-((R)-3-methylmorpholino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-((R)-3-methylpiperazin-1-yl)phenyl)urea

Prepared as shown in Scheme 7, using (R)-tert-butyl4-(4-aminophenyl)-3-methylpiperazine-1-carboxylate in the urea formationstep. Following urea formation, the Boc-piperazine intermediate wastreated with TFA to provide the title compound. Yield; 68 mg (90%);(M+H) 573.3.

Preparation of (R)-tert-butyl4-(4-aminophenyl)-3-methylpiperazine-1-carboxylate

Prepared from 4-fluoronitrobenzene and the appropriate amine as shown inScheme 4.

Example 425 Preparation of1-(4-((3R,5S)-3,5-dimethylpiperazin-1-yl)phenyl)-3-(4-(4-((R)-3-methylmorpholino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)urea

Prepared as shown in Scheme 7, using (3,5-cis)-tert-butyl4-(4-aminophenyl)-3,5-dimethylpiperazine-1-carboxylate in the ureaformation step. Following urea formation, the Boc-piperazineintermediate was treated with TFA to provide the title compound. Yield;67 mg (77%); (M+H) 587.3.

Preparation of (3,5-cis)-tert-butyl4-(4-aminophenyl)-3,5-dimethylpiperazine-1-carboxylate

Prepared from 4-fluoronitrobenzene and the appropriate amine as shown inScheme 4.

Example 426 Preparation of1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-sulfoxymorpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea

Prepared as shown in Scheme 6. A solution of1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-thiomorpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea(0.020 g, 0.033 mmol) in acetonitrile (1.5 ml) and water (0.5 ml) wasprepared and oxone (0.020 g, 0.033 mmol) was added. The solution wasstirred at room temperature for 16 hours. The suspension was dilutedwith ethyl acetate and washed with saturated sodium bicarbonate. Theorganic phase was washed with brine, dried, and concentrated, thenpurified by HPLC (5-95% acetonitrile in water over 20 minutes, 0.05% TFAbuffer, Waters Atlantis column) to provide the TFA salt of the sulfoxideof1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-sulfoxymorpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea(0.0029 g, 14%) as a white solid. (M+H) 618.4.

Example 427 Preparation of(R)-1-(4-(2-(dimethylamino)ethoxy)phenyl)-3-(4-(4-(3-methylmorpholino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)urea

Prepared as shown in Scheme 7, using 4-(2-(dimethylamino)ethoxy)anilinein the urea formation step. Yield; 34 mg (51%); (M+H) 562.3.

Example 428 Preparation of(R)-1-(4-(4-ethylpiperazin-1-yl)phenyl)-3-(4-(4-(3-methylmorpholino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)urea

Prepared as shown in Scheme 7, using commercially available4-(4-ethylpiperazin-1-yl)aniline in the urea formation step. Yield; 66mg (93%); (M+H) 587.3.

Example 429 Preparation of(R)-1-(4-(4-isopropylpiperazin-1-yl)phenyl)-3-(4-(4-(3-methylmorpholino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)urea

Prepared as shown in Scheme 7, using4-(4-isopropylpiperazin-1-yl)aniline in the urea formation step. Yield;66 mg (91%); (M+H) 601.4.

Preparation of 4-(4-isopropylpiperazin-1-yl)aniline

Prepared from 4-fluoronitrobenzene and the appropriate amine as shown inScheme 4.

Example 430 Preparation of(R)-1-(4-(4-(dimethylamino)piperidin-1-yl)phenyl)-3-(4-(4-(3-methylmorpholino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)urea

Prepared as shown in Scheme 7, using1-(4-aminophenyl)-N,N-dimethylpiperidin-4-amine in the urea formationstep. Yield; 69 mg (95%); (M+H) 601.4.

Example 431 Preparation of(R)-1-(4-(4-(3-methylmorpholino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazine-1-carbonyl)phenyl)urea

Prepared as shown in Scheme 7, using(4-aminophenyl)(4-methylpiperazin-1-yl)methanone in the urea formationstep. Yield; 38 mg (52%); (M+H) 601.3.

The (4-aminophenyl)(piperazin-1-yl)methanone intermediates prepared asshown in Scheme 8 were used to make the following compounds.

Example 432 Preparation of(R)-1-(4-(4-isopropylpiperazine-1-carbonyl)phenyl)-3-(4-(4-(3-methylmorpholino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)urea

Prepared as shown in Scheme 7, using(4-aminophenyl)(4-isopropylpiperazin-1-yl)methanone in the ureaformation step. Yield; 68 mg (89%); (M+H) 629.3.

Preparation of (4-aminophenyl)(4-isopropylpiperazin-1-yl)methanone

Prepared from 4-nitrobenzoyl chloride and the appropriate amine as shownin Scheme 8.

Example 433 Preparation of(R)-1-(4-(4-(3-methylmorpholino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)urea

Prepared as shown in Scheme 7, using commercially available6-(4-methylpiperazin-1-yl)pyridin-3-amine in the urea formation step.Yield; 69 mg (99%); (M+H) 574.3.

Example 434 Preparation of1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-ethylpiperazin-1-yl)phenyl)urea

Prepared as shown in Scheme 7, using commercially available4-(4-ethylpiperazin-1-yl)aniline in the urea formation step. Yield; 32mg (43%); (M+H) 599.3.

Example 435 Preparation of1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazin-1-yl)phenyl)urea

Prepared as shown in Scheme 7, using4-(4-isopropylpiperazin-1-yl)aniline in the urea formation step. Yield;51 mg (66%); (M+H) 613.4.

Example 436 Preparation of1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-cyclopropylpiperazin-1-yl)phenyl)urea

Prepared as shown in Scheme 7, using4-(4-cyclopropylpiperazin-1-yl)aniline in the urea formation step.Yield; 11 mg (14%); (M+H) 611.3.

Preparation of 4-(4-cyclopropylpiperazin-1-yl)aniline

Prepared from 4-fluoronitrobenzene and the appropriate amine as shown inScheme 4.

Example 437 Preparation of1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(dimethylamino)piperidin-1-yl)phenyl)urea

Prepared as shown in Scheme 7, using1-(4-aminophenyl)-N,N-dimethylpiperidin-4-amine in the urea formationstep. Yield; 28 mg (36%); (M+H) 613.4.

Example 438 Preparation of1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazine-1-carbonyl)phenyl)urea

Prepared as shown in Scheme 7, using(4-aminophenyl)(4-methylpiperazin-1-yl)methanone in the urea formationstep. Yield; 36 mg (46%); (M+H) 613.3.

Example 439 Preparation of1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazine-1-carbonyl)phenyl)urea

Prepared as shown in Scheme 7, using(4-aminophenyl)(4-isopropylpiperazin-1-yl)methanone in the ureaformation step. Yield; 41 mg (50%); (M+H) 641.3.

The following1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-ureacompounds were prepared as shown in Scheme 9.

Example 440 Preparation of1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-ethylpiperazin-1-yl)phenyl)ureaStep 1: Preparation of(R)-4-(4-chloro-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)-3-methylmorpholine

A solution of 2,4-dichloro-6-(4-nitrophenyl)-1,3,5-triazine (1.25 g,4.61 mmol) and sodium bicarbonate (0.775 g, 9.22 mmol) in acetone (20mL) and ice water (20 mL) was prepared. To this was added dropwise over5 minutes (R)-3-methylmorpholine (0.466 g, 4.61 mmol). The resulting tansolution was allowed to stir at 0° C. for 2 hours, then graduallyallowed to warm to room temperature over 18 hours. The light brownsuspension was filtered and washed with water to provide(R)-4-(4-chloro-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)-3-methylmorpholine(1.40 g, 90%) as a light brown solid. HRMS 336.0857 (M+H, calc.),336.0845 (M+H, obs.).

Step 2: Preparation of8-(4-((R)-3-methylmorpholino)-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)-3-oxa-8-azabicyclo[3.2.1]octane:

A solution of(R)-4-(4-chloro-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)-3-methylmorpholine(0.94 g, 2.80 mmol) in acetone (10 mL) and ice water (10 mL) wasprepared. To this was added dropwise over 10 minutes a suspension of3-oxa-8-azabicyclo[3.2.1]octane-hydrochloride (0.419 g, 2.80 mmol) andsodium bicarbonate (0.470 g, 5.60 mmol) in acetone (10 mL) and water (10mL). The resulting tan solution was allowed to stir at 0° C. for 2hours, then gradually allowed to warm to room temperature over 3 hours.The light brown suspension was filtered and washed with water to provide8-(4-chloro-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)-3-oxa-8-azabicyclo[3.2.1]octane(0.964 g, 83%) as a brown solid. HRMS 413.1931 (M+H, calc.), 413.1936(M+H, obs.).

Step 3: Preparation of4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)aniline

A solution of8-(4-((R)-3-methylmorpholino)-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)-3-oxa-8-azabicyclo[3.2.1]octane(0.915 g, 2.22 mmol) in ethyl acetate (10 ml), methanol (10 ml), andmethylene chloride (5 ml—added due to poor solubility of SM inEA/methanol) was prepared and 10% palladium on carbon (0.270 g, 30% byweight) was added. The flask was purged with hydrogen gas (balloon) andallowed to stir under positive pressure of hydrogen for 16 hours. Thesuspension was filtered through Celite™, the filter cake was washed withethyl acetate, and the filtrate was concentrated to provide4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)aniline(0.587 g, 69%) as an off-white solid. (M+H) 383.3.

Step 4: Preparation of1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-ethylpiperazin-1-yl)phenyl)urea

The method of urea formation using triphosgene and triethylamine inmethylene chloride, described in Scheme 1, was utilized usingcommercially available 4-(4-ethylpiperazin-1-yl)aniline as the aminecomponent. Purification by HPLC (5-95% acetonitrile in water over 20minutes, 0.05% TFA buffer, Waters Atlantis column) provided1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-ethylpiperazin-1-yl)phenyl)urea(0.0761 g, 95%) as a light yellow solid. (M+H) 614.3.

Example 441 Preparation of1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazin-1-yl)phenyl)urea

Prepared as shown in Scheme 9, using4-(4-isopropylpiperazin-1-yl)aniline in the urea formation step. Yield;82 mg (100%); (M+H) 628.4.

Example 442 Preparation of1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-cyclopropylpiperazin-1-yl)phenyl)urea

Prepared as shown in Scheme 9, using4-(4-cyclopropylpiperazin-1-yl)aniline in the urea formation step.Yield; 32 mg (39%); (M+H) 626.3.

Example 443 Preparation of1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(dimethylamino)piperidin-1-yl)phenyl)urea

Prepared as shown in Scheme 9, using1-(4-aminophenyl)-N,N-dimethylpiperidin-4-amine in the urea formationstep. Yield; 77 mg (93%); (M+H) 628.4.

Example 444 Preparation of1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazine-1-carbonyl)phenyl)urea

Prepared as shown in Scheme 9, using(4-aminophenyl)(4-methylpiperazin-1-yl)methanone in the urea formationstep. Yield; 43 mg (52%); (M+H) 628.3.

Example 445 Preparation of1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazine-1-carbonyl)phenyl)urea

Prepared as shown in Scheme 9, using(4-aminophenyl)(4-isopropylpiperazin-1-yl)methanone in the ureaformation step. Yield; 72 mg (84%); (M+H) 656.4.

Example 446 Preparation of1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)urea

Prepared as shown in Scheme 9, using commercially available6-(4-methylpiperazin-1-yl)pyridin-3-amine in the urea formation step.Yield; 74 mg (94%); (M+H) 601.3.

Example 447 Preparation of1-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-ethylpiperazin-1-yl)phenyl)urea

Prepared as shown in Scheme 1, using commercially available4-(4-ethylpiperazin-1-yl)aniline in the urea formation step. Yield; 80mg (99%); (M+H) 602.3.

Example 448 Preparation of1-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazin-1-yl)phenyl)urea

Prepared as shown in Scheme 1, using4-(4-isopropylpiperazin-1-yl)aniline in the urea formation step. Yield;74 mg (88%); (M+H) 616.4.

Example 449 Preparation of1-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(dimethylamino)piperidin-1-yl)phenyl)urea

Prepared as shown in Scheme 1, using1-(4-aminophenyl)-N,N-dimethylpiperidin-4-amine in the urea formationstep. Yield; 80 mg (96%); (M+H) 616.4.

Example 450 Preparation of1-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazine-1-carbonyl)phenyl)urea

Prepared as shown in Scheme 1, using(4-aminophenyl)(4-methylpiperazin-1-yl)methanone in the urea formationstep. Yield; 79 mg (95%); (M+H) 616.3.

Example 451 Preparation of1-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazine-1-carbonyl)phenyl)urea

Prepared as shown in Scheme 1, using(4-aminophenyl)(4-isopropylpiperazin-1-yl)methanone in the ureaformation step. Yield; 18 mg (20%); (M+H) 644.4.

Example 452 Preparation of4-(3-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)ureido)-N,N-dimethylbenzamide

Prepared as shown in Scheme 1, using commercially available4-amino-N,N-dimethylbenzamide in the urea formation step. Yield; 43 mg(57%); (M+H) 561.3.

Example 453 Preparation of1-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(pyrrolidin-1-ylmethyl)phenyl)urea

Prepared as shown in Scheme 1, using commercially available4-(pyrrolidin-1-ylmethyl)aniline in the urea formation step. Yield; 61mg (79%); (M+H) 573.3.

Example 454 Preparation of4-(3-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)ureido)benzamide

Prepared as shown in Scheme 7, using commercially available4-aminobenzamide in the urea formation step. Yield; 22 mg (21%); (M+H)530.2.

Example 455 Preparation of4-(3-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)ureido)-N,N-dimethylbenzamide

Prepared as shown in Scheme 7, using commercially available4-amino-N,N-dimethylbenzamide in the urea formation step. Yield; 22 mg(21%); (M+H) 558.3.

Example 456 Preparation of1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(pyrrolidine-1-carbonyl)phenyl)urea

Prepared as shown in Scheme 7, using(4-aminophenyl)(pyrrolidin-1-yl)methanone in the urea formation step.Yield; 41 mg (36%); (M+H) 584.3.

Preparation of (4-aminophenyl)(pyrrolidin-1-yl)methanone

Prepared from 4-nitrobenzoyl chloride and the appropriate amine as shownin Scheme 8.

Example 457 Preparation of4-(3-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)ureido)-N-(2-(dimethylamino)ethyl)benzamide

Prepared as shown in Scheme 7, using4-amino-N-(2-(dimethylamino)ethyl)benzamide in the urea formation step.Yield; 36 mg (32%); (M+H) 601.3.

Preparation of 4-amino-N-(2-(dimethylamino)ethyl)benzamide

Prepared from 4-nitrobenzoyl chloride and the appropriate amine as shownin Scheme 8.

Example 458 Preparation of4-(3-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)ureido)-N-(2-(methylamino)ethyl)benzamide

Prepared as shown in Scheme 7, using tert-butyl2-(4-aminobenzamido)ethyl(methyl)carbamate in the urea formation step.Following urea formation, the Boc-amine intermediate was treated withTFA to provide the title compound. Yield; 25 mg (22%); (M+H) 587.3.

Preparation of tert-butyl 2-(4-aminobenzamido)ethyl(methyl)carbamate

Prepared from 4-nitrobenzoyl chloride and the appropriate amine as shownin Scheme 8.

Example 459 Preparation of4-(3-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)ureido)-N-(2-(dimethylamino)ethyl)-N-methylbenzamide

Prepared as shown in Scheme 7, using4-amino-N-(2-(dimethylamino)ethyl)-N-methylbenzamide in the ureaformation step. Yield; 10 mg (9%); (M+H) 615.3.

Preparation of 4-amino-N-(2-(dimethylamino)ethyl)-N-methylbenzamide

Prepared from 4-nitrobenzoyl chloride and the appropriate amine as shownin Scheme 8.

Example 460 Preparation of1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(morpholine-4-carbonyl)phenyl)urea

Prepared as shown in Scheme 7, using(4-aminophenyl)(morpholino)methanone in the urea formation step. Yield;25 mg (21%); (M+H) 600.3.

Preparation of (4-aminophenyl)(morpholino)methanone

Prepared from 4-nitrobenzoyl chloride and the appropriate amine as shownin Scheme 8.

Example 461 Preparation of1-(4-(2-aminoethylamino)phenyl)-3-(4-(4,6-di(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)urea:

Prepared as shown in Scheme 1, using di-Boc protectedN1-(2-aminoethyl)benzene-1,4-diamine in the urea formation step.Following urea formation, the di-Boc-amine intermediate was treated withTFA to provide the title compound. Yield; x mg (x %); HRMS 572.3092(M+H, calc.), 572.3098 (M+H, obs.).

Preparation of di-Boc protected N1-(2-aminoethyl)benzene-1,4-diamine

Prepared from 4-fluoronitrobenzene and the appropriate amine as shown inScheme 4.

Example 462 Preparation of4-({[4-(4-{4-[(methylcarbamoyl)amino]phenyl}-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzamide Step 1: Preparation of phenyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate

To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline(25.0 g, 114 mmol) and pyridine (4 mL, 57 mmol) in dry dichloromethane(250 mL) phenyl chloroformate (12 mL, 114 mmol) was added drop wise at−10° C. The reaction mixture was stirred at −10° C. for 30 min and thenat room temperature for 30 minutes. The reaction mixture was dilutedwith dichloromethane (100 mL) and washed with water (2×70 mL). Theorganic layer was dried over anhydrous Na₂SO₄ and concentrated to getthe crude product. Then the crude product was dissolved in diethyl ether(15 mL) and sonicated for 10 min and then pentane (30 mL) was added. theresulting solid was filtered and washed with pentane to give phenyl4-(4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate (26 g,88% yield).

¹HNMR (300 MHz, CDCl₃): δ7.8 (d, 2H) 7.5 (d, 2H), 7.4 (m, 2H), 7.2 (m,3H), 7.0 (s, 1H), 1.3 (s, 12H).

Step 2: Preparation of 1-methyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea

A mixture of phenyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate (26 g,76.6 mmol)), 2.0M Methylamine/THF (265 mL, 530 mmol) in 150 mL of THFwas stirred at room temperature for 6 hours, then excess solvent wasdistilled off from the reaction mixture; residue was dissolved intowater, extracted with ethyl acetate. The organic layer was dried overanhydrous Na₂SO₄, concentrated under reduced pressure. The crude productwas purified by silica gel column chromatography by using 5-60% ethylacetate in pet-ether as an eluent. to give1-methyl-3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-urea.(20 g, 88% yield) as white solid.

¹HNMR (300 MHz, CDCl₃): δ7.7 (d, 2H), 7.2 (d, 2H), 6.7 (s, 1H), 5.0 (s,1H), 2.8 (s, 3H), 1.2 (s, 12H).

Step 3: Preparation of 4-(4,6-dichloro-1,3,5-triazin-2-yl) morpholine

Morpholine (9.5 mL, 108 mmol)) was added to a solution of cyanuricchloride (20 g, 108 mmol) in chloroform (10 mL) and stirred at −5° C.for 1 hour. Reaction mixture was diluted with water, extracted withdichloromethane. The organic layer was dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure. Crude product waspurified by silica gel (100-200 mesh) column chromatography using 5%ethyl acetate in pet-ether as an eluent to give4-(4,6-dichloro-1,3,5-triazin-2-yl)morpholine (10 g, 39% yield).

Step 4: Preparation of1-(4-(4-chloro-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-methylurea

A mixture of compound 4-(4,6-dichloro-1,3,5-triazin-2-yl)morpholine (10g, 42.7 mmol), Pd (PPh₃)₄ (2.46 g, 2.1 mmol),1-methyl-3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-urea.(11.7 g, 42.4 mmol) and 1 N Na₂CO₃ (168 mL, 168 mmol) in degassed1,2-dimethoxyethane (400 mL) was heated to 65° C. for 8 hours under N₂atmosphere. The reaction mixture filtered, diluted with water, extractedwith ethyl acetate and washed with water, brine, dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure. Crude productwas purified by silica gel (100-200 mesh) column chromatography using20-60% ethyl acetate in pet-ether as an eluent. To give1-(4-(4-chloro-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-methylurea (5.0g, 34% yield).

¹HNMR (300 MHz, DMSO-d6): δ 9.4 (br, 1H), 8.2 (d, 2H), 7.6 (d, 2H), 6.6(br, 1H), 4.0 (m, 2H), 3.8 (m, 6H), 2.8 (s, 3H).

Step 5: Preparation of1-(4-(4-(4-aminophenyl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-methylurea

The title compound was prepared by following the procedure of Example462 step 4 using1-(4-(4-chloro-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-methylurea and4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline. Yield 2 g, 45%yield.

Step 6: Preparation of phenyl 4-carbamoylphenylcarbamate

To a solution of 4-aminobenzamide (5.0 g, 36.7 mmol) and pyridine (2.9g, 36.7 mmol)) in dry CH₂Cl₂ (100 mL) at −10° C., phenyl chloroformate(6.9 g, 44.1 mmol) was added dropwise, stirred at −10° C. for 30 min andthen at room temperature for 30 minutes The reaction mixture was dilutedwith CH₂Cl₂ (100 mL) and washed with water (2×70 mL). The organic layerwas dried over anhydrous Na₂SO₄ and concentrated to get the crudeproduct. The crude product was dissolved in diethyl ether (15 mL) andsonicated for 10 minutes and then pentane (30 mL) was added, theresulting solid was filtered and washed with pentane to give phenyl4-carbamoylphenylcarbamate (7.2 g, 77% yield).

Step 7: Preparation of4-({[4-(4-{4-[(methylcarbamoyl)amino]phenyl}-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzamide

To a solution of1-(4-(4-(4-aminophenyl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-methylurea(0.6 g, 1.5 mmol) and triethylamine(4-5 mL) in dry DMF (10 mL), phenyl4-carbamoylphenylcarbamate (1.15 g, 4.5 mmol).) was added at roomtemperature and mixture was heated to 90° C. for 10 hours under nitrogenatmosphere. After cooling to room temperature reaction mixture wasquenched with ice water and resulting solid was filtered to get crudeproduct. Crude product was purified by Preparative HPLC to give4-({[4-(4-{4-[(methylcarbamoyl)amino]phenyl}-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzamide(45 mg, 5.3% yield).

Example 463 Preparation of1-{4-[4-(3,5-dimethylmorpholin-4-yl)-6-{4-[(methylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylureaStep 1: Preparation of4-(4,6-dichloro-1,3,5-triazin-2-yl)-3,5-dimethylmorpholine

The title compound was prepared by following the procedure of Example462 step 3 using cyanuric chloride and 3,5-dimethylmorpholine. Yield 5g, 35% yield.

¹HNMR (300 MHz, CDCl₃): δ 4.6 (m, 2H), 3.6 (m, 2H), 2.8 (m, 2H), 1.2 (d,6H).

Step 2: Preparation of1-(4-(4-chloro-6-(3,5-dimethylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-methylurea

The title compound was prepared by following the procedure of example462 step 4 using4-(4,6-dichloro-1,3,5-triazin-2-yl)-3,5-dimethylmorpholine and1-methyl-3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-urea.Yield 1.15 g, 16% yield.

Step 3: Preparation of 1-(4-(4-(4-aminophenyl)-6-(3,5-dimethylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-methylurea

The title compound was prepared by following the procedure of example462 step 4 using1-(4-(4-chloro-6-(3,5-dimethylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-methylureaand 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline. Yield 2 g,86% yield.

Step 4: Preparation of phenyl pyridin-3-ylcarbamate

The title compound was prepared by following the procedure of example462 step 6 using 3-aminopyridine and phenyl chloroformate. Yield 7 g,62% yield.

Step 5: Preparation of1-{4-[4-(3,5-dimethylmorpholin-4-yl)-6-{4-[(methylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea

The title compound was prepared by following the procedure of example462 step 7 using1-(4-(4-(4-aminophenyl)-6-(3,5-dimethylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-methylureaand phenyl pyridin-3-ylcarbamate. Yield 77 mg, 6% yield.

Example 464 Preparation of4-[({4-[4-{4-[(methylcarbamoyl)amino]phenyl}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamideStep 1: Preparation of3-(4,6-dichloro-1,3,5-triazin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane

The title compound was prepared by following the procedure of example462 step 3 using cyanuric chloride and 8-oxa-3-azabicyclo[3.2.1]octane.Yield 10 g, 47% yield.

Step 2: Preparation of1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-chloro-1,3,5-triazin-2-yl)phenyl)-3-methylurea

The title compound was prepared by following the procedure of example462 step 4 using3-(4,6-dichloro-1,3,5-triazin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane and1-methyl-3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-urea.Yield 5 g, 29% yield.

Step 3: Preparation of1-(4-(4-(4-aminophenyl)-6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1,3,5-triazin-2-yl)phenyl)-3-methylurea

The title compound was prepared by following the procedure of example462 step 4 using1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-chloro-1,3,5-triazin-2-yl)phenyl)-3-methylureaand 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline. Yield 2.8 g,49% yield.

Step 4: Preparation of4-[({4-[4-{4-[(methylcarbamoyl)amino]phenyl}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide

The title compound was prepared by following the procedure of example462 step 7 using1-(4-(4-(4-aminophenyl)-6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1,3,5-triazin-2-yl)phenyl)-3-methylureaand phenyl 4-carbamoylphenylcarbamate. Yield 90 mg, 13% yield.

Example 465 Preparation of3-[({4-[4-{4-[(methylcarbamoyl)amino]phenyl}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamideStep 1: Preparation of phenyl 3-carbacarbamoylphenylcarbamate

The title compound was prepared by following the procedure of example462 step 6 using 3-aminobenzamide and phenyl chloroformate. Yield 7 g,74% yield.

Step 2: Preparation of3-[({4-[4-{4-[(methylcarbamoyl)amino]phenyl}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide

The title compound was prepared by following the procedure of example462 step 7 using1-(4-(4-(4-aminophenyl)-6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1,3,5-triazin-2-yl)phenyl)-3-methylureaand phenyl 3-carbamoylphenylcarbamate. Yield 90 mg, 13% yield.

Example: 466 Preparation of3-({[4-(4-{4-[(methylcarbamoyl)amino]phenyl}-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzamide

The title compound was prepared by following the procedure of example462 step 7 using1-(4-(4-(4-aminophenyl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-methylureaand phenyl 3-carbamoylphenylcarbamate. Yield 51 mg, 4% yield.

Example 467 Preparation of1-methyl-3-[4-(4-morpholin-4-yl-6-{4-[(pyridin-3-ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl)phenyl]urea

The title compound was prepared by following the procedure of example462 step 7 using1-(4-(4-(4-aminophenyl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-methylureaand phenyl pyridin-3-ylcarbamate. Yield 77 mg, 6% yield.

Example 468 Preparation of1-methyl-3-[4-(4-morpholin-4-yl-6-{4-[(pyridin-4-ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl)phenyl]ureaStep 1: Preparation of phenyl pyridin-4-ylcarbamate

The title compound was prepared by following the procedure of example462 step 6 using 4-aminopyridine and phenyl chloroformate. Yield 6 g,534% yield.

Step 2: Preparation of1-methyl-3-[4-(4-morpholin-4-yl-6-{4-[(pyridin-4-ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl)phenyl]urea

The title compound was prepared by following the procedure of example462 step 7 using1-(4-(4-(4-aminophenyl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-methylureaand phenyl pyridin-4-ylcarbamate. Yield 75 mg, 3.9% yield.

Example 469 Preparation of3-[({4-[4-(3,5-dimethylmorpholin-4-yl)-6-{4-[(methylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide

The title compound was prepared by following the procedure of example462 step 7 using1-(4-(4-(4-aminophenyl)-6-(3,5-dimethylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-methylureaand phenyl 3-carbamoylphenylcarbamate. Yield 56 mg, 4.1% yield.

Example 470 Preparation of4-[({4-[4-(3,5-dimethylmorpholin-4-yl)-6-{4-[(methylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide

The title compound was prepared by following the procedure of example462 step 7 using1-(4-(4-(4-aminophenyl)-6-(3,5-dimethylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-methylureaand phenyl 4-carbamoylphenylcarbamate. Yield 70 mg, 12.8% yield.

Example 471 Preparation of1-methyl-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-{4-[(pyridin-4-ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl]phenyl}urea

The title compound was prepared by following the procedure of example462 step 7 using1-(4-(4-(4-aminophenyl)-6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1,3,5-triazin-2-yl)phenyl)-3-methylureaand phenyl pyridin-4-ylcarbamate. Yield 51 mg, 4% yield.

Example 472 Preparation of1-{4-[4-(3,5-dimethylmorpholin-4-yl)-6-{4-[(methylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea

The title compound was prepared by following the procedure of example462 step 7 using1-(4-(4-(4-aminophenyl)-6-(3,5-dimethylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-methylureaand phenyl pyridin-4-ylcarbamate. Yield 15 mg, 0.8% yield.

Example 473 Preparation ofN-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-2,2-difluoroacetamideStep 1: Preparation of4,4′-(6-chloro-1,3,5-triazine-2,4-diyl)dimorpholine

A solution of morpholine (8.71 g, 100 mmol) in 100 mL of methylene wasadded dropwise to a mixture of cyanuric chloride (9.22 g, 50.0 mmol) andtriethylamine (10.1 g, 100 mmol) in 200 mL of methylene chloride at 0°C. Then the reaction mixture was stirred at 0° C. for 1 hr and slowlywarmed up to room temperature. After stirring at room temperature for 1hr, the reaction mixture was filtered to remove the triethylaminehydrochloride salt. The filtrate was concentrated to give4,4′-(6-chloro-1,3,5-triazine-2,4-diyl) dimorpholine (14.2 g, 100 yield)as a white solid. HPLC: Rt=2.43 min; MS 286, 288 [M+H].

Step 2: Preparation of 4-(4,6-dimorpholino-1,3,5-triazin-2-yl)aniline

A mixture of 4,4′-(6-chloro-1,3,5-triazine-2,4-diyl)dimorpholine (1.40g, 4.90 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline(2.62 g, 11.9 mmol) and tetrakis(triphenylphosphine) palladium (0) (282mg, 0.240 mmol) in 2M sodium carbonate aqueous solution (10 mL, 20 mmol)and 40 mL of DME was stirred at 80° C. for 2 hr. The reaction mixturewas diluted with 300 mL of ethyl acetate and washed with water. Theorganic layer was concentrated and purified by flash chromatography(ISCO, 120 g silica gel column, eluting with 0-100% EtOAc/Hexane) togive 4-(4,6-dimorpholino-1,3,5-triazin-2-yl)aniline (0.68 g, 40% yield).HPLC: Rt=2.09 min; MS 343 [M+H].

Step 3: Preparation ofN-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-2,2-difluoroacetamide

To a mixture of 2,2-difluoroacetic acid (20 mg, 0.21 mmol), HBTU (76 mg,0.2 mmol), and DIEA (52 mg, 0.40 mmol) in 2 mL of DMF was added4-(4,6-dimorpholino-1,3,5-triazin-2-yl) aniline (40 mg, 0.12 mmol). Thereaction was stirred at 60° C. 16 hr. Then the reaction mixture wascooled to room temperature and purified by reverse phase chromatographyto giveN-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-2,2-difluoroacetamide(23 mg, 46% yield). HPLC: Rt=2.19 min; MS 421 [M+H].

Example 474 Preparation ofN-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-4,5-dihydro-1H-imidazol-2-amine

A mixture of 4-(4,6-dimorpholino-1,3,5-triazin-2-yl)aniline (40 mg, 0.12mmol), imidazolidine-2-thione (15 mg, 0.15 mmol 0 and mercury(II)chloride (40 mg, 0.15 mmol) in 2 mL of DMF was stirred at 140° C. 16 hr.Then the reaction mixture was cooled to room temperature and filteredthrough Celite™. The filtration was concentrated and purified by reversephase chromatography to giveN-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-4,5-dihydro-1H-imidazol-2-amine(9.0 mg, 22% yield). HPLC: Rt=1.74 min; MS 411 [M+H].

Example 475 Preparation of2,4-dimorpholin-4-yl-6-[4-(2H-tetrazol-5-yl)phenyl]-1,3,5-triazine Step1: Preparation of 4-(4,6-dimorpholino-1,3,5-triazin-2-yl)benzonitrile

The title compound was prepared by following the procedure of example473 step 2 using 4,4′-(6-chloro-1,3,5-triazine-2,4-diyl) dimorpholineand 4-cyanophenyl-boronic acid. Yield 86 mg, 50% yield; HPLC: Rt=2.60min; MS 353 [M+H].

Step 2: Preparation of2,4-dimorpholin-4-yl-6-[4-(2H-tetrazol-5-yl)phenyl]-1,3,5-triazine

A mixture of 4-(4,6-dimorpholino-1,3,5-triazin-2-yl)benzonitrile (11 mg,0.031 mmol), sodium azide (5.5 mg, 0.085 mmol) and triethylaminehydrochloride (6.0 mg, 0.043 mmol) in 2 mL of DMF was stirred at 120° C.for 6 hr. Then the reaction mixture was cooled to room temperature andpurified by reverse phase chromatography to give2,4-dimorpholin-4-yl-6-[4-(2H-tetrazol-5-yl)phenyl]-1,3,5-triazine.Yield 12 mg, 97% yield; HPLC: Rt=2.09 min; MS 394 [M−H].

Example 476 Preparation of1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-methylurea Step1: Preparation of 1-Methyl-3-[4-(4, 4,5,5-tetramethyl-[1, 3,2]dioxaborolan-2-yl)-phenyl]-urea

A mixture of2-(4-isocyanatophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (750 mg,3.06 mmol), 2.0M Methylamine/THF (2.3 mL, 4.60 mmol) in 50 mL of THF wasstirred at room temperature for 6 hr. Then the traction mixture wasconcentrated to give 1-methyl-3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-urea. (760 mg, 90%yield). Rt=2.21 min; 277 [M+H].

Step 2: Preparation of1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-methylurea

The title compound was prepared by following the procedure of example473 step 2 using 4,4′-(6-chloro-1,3,5-triazine-2,4-diyl)dimorpholine and1-Methyl-3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-urea.Yield 13 mg, 11% yield; HPLC: Rt=1.98 min; MS 400 [M+H].

Example 477 Preparation of2-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-N-pyridin-3-ylacetamideStep 1: Preparation of2-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)acetic acid

A mixture of 4,4′-(6-chloro-1,3,5-triazine-2,4-diyl)dimorpholine (285mg, 1.0 mmol),2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetic acid.(315 mg, 1.2 mmol) and tetrakis (triphenylphosphine) palladium (0) (58mg, 0.05 mmol) in 2M sodium carbonate aqueous solution (3 mL, 8 mmol)and 20 mL of DME was stirred at 80° C. for 2 hr. Then the reactionmixture was diluted with 50 mL of ethyl acetate and extracted with 1 NNaOH (50 mL, three times)). The combined aqueous layers were neutralizedto pH=6. Then the aqueous solution was extracted with ethyl acetate (50mL, three times). The combined organic layers were washed with saturatedsodium carbonate and brine. Then the organic layer was dried overanhydrous sodium sulfate and concentrated to give2-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)acetic acid (68 mg, 18%yield). HPLC: Rt=2.04 min; MS 386 [M+H].

Step 2: Preparation of2-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-N-pyridin-3-ylacetamide

The title compound was prepared by following the procedure of example473 step 3 using 2-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)aceticacid and 3-aminopyridine. Yield 21 mg, 44% yield; HPLC: Rt=1.91 min; MS462 [M+H].

Preparation of((2S,5R)-1-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)pyrrolidine-2,5-diyl)dimethanol

A suspension of((2S,5R)-1-(4-chloro-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)pyrrolidine-2,5-diyl)dimethanol(1.3 g, 2.7 mmol), 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride (0.51g, 3.4 mmol) in ethanol (15 mL) was treated with triethylamine (1.35 mL,10 mmol) and heated with a heat gun briefly to reflux. The reactionmixture was purified by automated flash chromatography(methanol/chloroform) to provide the title compound as a hard peachcolored foam. MS (ES⁺)=443.2 (M+H)⁺.

Preparation of3-(4-((2S,5R)-2,5-bis((tert-butyldimethylsilyloxy)methyl)pyrrolidin-1-yl)-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane

A solution of((2S,5R)-1-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)pyrrolidine-2,5-diyl)dimethanol(1.5 g, 3.4 mmol) in dichloromethane (15 mL) was treated successivelywith tert-butyl dimethyl chlorosilane (1.3 g, 8.5 mmol) and imidazole(0.69 g, 10 mmol). The resulting suspension was stirred overnight atroom temperature and then quenched with water. The aqueous phase wasextracted three times with dichloromethane. The combined extracts weredried over anhydrous magnesium sulfate, filtered, and concentrated todryness under reduced pressure. The crude residue (a peach-coloredsolid) was carried on to the following step without furtherpurification. MS (ES⁺)=671.4 (M+H)⁺.

Preparation of4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2S,5R)-2,5-bis((tert-butyldimethylsilyloxy)methyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)aniline

A suspension of palladium on charcoal (10%, 100 mg) and crude3-(4-((2S,5R)-2,5-bis((tert-butyldimethylsilyloxy)methyl)pyrrolidin-1-yl)-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane(3.4 mmol maximum) in tetrahydrofuran (30 mL) was shaken for 8 hoursunder 50 psi of hydrogen. The mixture was filtered through a pad ofCelite™ diatomaceous earth and concentrated under reduced pressure toprovide the title compound as an orange foam. MS (ES⁺)=642.4 (M+H)⁺.

Example 667 Preparation of1-(4-{4-[(2R,5S)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea

A solution of4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2S,5R)-2,5-bis((tert-butyldimethylsilyloxy)methyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)aniline(0.24 g, 0.37 mmol) in dichloromethane (5 mL) was treated successivelywith triethylamine (500 μL) and a triphosgene (56 mg) solution indichloromethane (1 mL). After 5 minutes, the mixture was treated with asolution of 4-aminopyridine (70 mg) in warm tetrahydrofuran. After 1hour, the reaction mixture was quenched with methanol and concentratedto dryness. Half of the crude residue was treated with a saturatedsolution of hydrogen chloride in methanol. Upon complete desilylation,the mixture was concentrated to dryness and the residue purified byreverse-phase high performance liquid chromatography using a PhenomenexProdigy column running a gradient elution of 5% acetonitrile/95% of 0.1%aqueous trifluoroacetic acid to 50% acetonitrile over 25 minutes. Afterconcentration, the title compound was obtained as it trifluoroaceticacid salt (75 mg). MS (ES⁺)=533.3 (M+H)⁺.

Example 668 Preparation of1-(4-{4-[(2R,5S)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-[4-(4-methylpiperazin-1-yl)phenyl]urea

A solution of4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2S,5R)-2,5-bis((tert-butyldimethylsilyloxy)methyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)aniline(0.25 g, 0.39 mmol) in dichloromethane (5 mL) was treated successivelywith triethylamine (500 μL) and a triphosgene (59 mg, 0.08 mmol)solution in dichloromethane (1 mL). After 5 minutes, the mixture wastreated with 4-(4-methylpiperazin-1-yl)aniline (150 mg). After 1 hour,the reaction mixture was quenched with methanol and concentrated todryness. The crude residue was treated with a saturated solution ofhydrogen chloride in methanol. Upon complete desilylation, the mixturewas concentrated to dryness and the residue purified by reverse-phasehigh performance liquid chromatography using a Phenomenex Gemini columnrunning a gradient elution of 5% acetonitrile/55% of 0.1% aqueoustrifluoroacetic acid to 50% acetonitrile over 15 minutes. Afterconcentration, the title compound was obtained as it trifluoroaceticacid salt (130 mg). MS (ES⁺)=630.4 (M+H)⁺.

Example 823 Preparation of1-[4-(4,6-di-3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(4-methylpiperazin-1-yl)phenyl]urea

To a solution of cyanuric chloride (0.368 g, 2 mmol) in CH₂Cl₂ (20 mL)was added 3,7-dioxa-9-azabicyclo[3.3.1]nonane. HCO₂H (0.718 g, 4.1mmol), followed by addition of Et₃N (0.98 mL, 7 mmol). The resultingreaction mixture was stirred for 24 h, and then diluted with CH₂Cl₂. Theorganic phase was washed with aqueous 1 N HCl (3×) and dried over MgSO₄.The solvent was removed in vacuum to give9,9′-(6-chloro-1,3,5-triazine-2,4-diyl)bis(3,7-dioxa-9-azabicyclo[3.3.1]nonane)as white solid (0.15 g, 95% yield).

To a 10 mL vial were added9,9′-(6-chloro-1,3,5-triazine-2,4-diyl)bis(3,7-dioxa-9-azabicyclo[3.3.1]nonane)(150 mg, 0.406 mmol), 4-aminophenylboronic acid pinacol ester (133 mg,0.61 mmol), Pd(PPh₃)₄ (10 mg), toluene (1 mL), EtOH (1 mL) and 2M Na₂CO₃aqueous solution (0.305 mL). The resulting mixture was heated at 120° C.for 20 minutes in microwave oven. The reaction mixture was cooled toroom temperature. The aqueous phase was extracted with EtOAc, and thecombined organic phases were dried over (MgSO₄). The solvent was removedunder reduced pressure and the residue was subjected to HPLC separationto give4-(4,6-di(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-1,3,5-triazin-2-yl)anilineas a white solid (120 mg).

To a solution of4-(4,6-di(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-1,3,5-triazin-2-yl)aniline(120 mg, 0.281 mmol) in CH₂Cl₂ was added Et₃N (0.237 mL, 1.69 mmol) andtriphosgene (42 mg, 0.14 mmol). The mixture was stirred at roomtemperature for 15 minutes and 4-(4-methylpiperazin-1-yl)aniline (107mg, 0.56 mmol) was added. The mixture was stirred at room temperatureovernight. The solvent was removed, and the residue was subjected toHPLC separation to give the title compound (1TFA salt) MS (ESI) m/z644.3306.

Preparation of (6S)-tert-butyl6-hydroxy-3-oxa-8-azabicyclo[3.2.1]octane-8-carboxylate (Scheme 10) Step1: (2R′,5S′)-1-tert-butyl 2,5-dimethyl1H-pyrrole-1,2,5(2H,5H)-tricarboxylate (cis-diester) was synthesized byfollowing the procedure described in literature: Organic Letters 2004,6(18), 3055-8. Step 2: Reduction of cis-diester to (2R′,5S′)-tert-butyl2,5-bis(hydroxymethyl)-2,5-dihydro-1H-pyrrole-1-carboxylate (cis-diol)

To a solution of (2R′,5S′)-1-tert-butyl 2,5-dimethyl1H-pyrrole-1,2,5(2H,5H)-tricarboxylate (6.6 g, 23.1 mmol) in THF (100mL) was added slowly of LiBH₄ solution (2M in THF, 34.7 mL, 69.4 mmol)at 0° C. The resulting mixture was stirred at room temperature for 3hours, then cooled to 0° C. again. HCl solution (1 M, 30 mL) was addedto the reaction mixture, and stirred for 10 minutes before diluted withEtOAc. The organic layer was separated, and the aqueous phase wasextracted with EtOAc. The combined organic phases were washed with waterand brine, and dried (MgSO₄). The organic solvent was removed in vacuoto give the crude product, which was purified by flash chromatography insilica gel with EtOAc:Hex:MeOH (50:50:10) to give the cis-diol (3.8 g,72%).

Step 3: Preparation of (2R′,5S′)-tert-butyl2,5-bis((tert-butyldimethylsilyloxy)methyl)-2,5-dihydro-1H-pyrrole-1-carboxylate

To a solution of the cis-diol (3.57 g, 15.6 mmol) in DMF (15 mL) wereadded TBSCl (5.16 g, 34.3 mmol) and imidazole (3.18 g, 46.7 mmol). Themixture was heated at 80° C. for 30 minutes in microwave oven (150 w).Cooled to room temperature, the mixture was taken up in water (50 mL)and EtOAc (50 mL). The organic layer was separated, and the aqueousphase was extracted with EtOAc. Combined organic phases were washed withwater and brine, and dried (MgSO₄). The organic solvent was removed invacuo to give the crude product, which was purified by flashchromatography in silica gel with EtOAc:Hex (10:90) to give the titlecompound (7.12 g, 98%).

Step 4: Synthesis of (2R′,3S′,5R′)-tert-butyl2,5-bis((tert-butyldimethylsilyloxy)methyl)-3-hydroxypyrrolidine-1-carboxylate(trans-alcohol)

To a solution of (2R′,5S′)-tert-butyl2,5-bis((tert-butyldimethylsilyloxy)methyl)-2,5-dihydro-1H-pyrrole-1-carboxylate(4.8 g, 10.5 mmol) in THF (50 mL) was added slowly of BH₃DMS solution(2M in THF, 6.97 mL, 13.9 mmol) at 0° C. The resulting mixture wasstirred at room temperature for 3 hours, then cooled to 0° C. again.NaOH solution (5M, 12.6 mL, 63.2 mmol) was added to the reactionmixture, followed by addition of H₂O₂ (30%, 6.33 mL, 62.0 mmol). Theresulting mixture was stirred for 5 hours before diluted with EtOAc. Theorganic layer was separated, and the aqueous phase was extracted withEtOAc. Combined organic phases were washed with water and brine, anddried (MgSO₄). The organic solvent was removed in vacuo to give thecrude product, which was purified by flash chromatography in silica gelwith EtOAc:Hex (30:70) to give the title compound (3.8 g, 77%).

Step 5: Benzyl Protection of the Trans Alcohol

To a solution of (2R′,3S′,5R′)-tert-butyl2,5-bis((tert-butyldimethylsilyloxy)methyl)-3-hydroxypyrrolidine-1-carboxylate(2.515 g, 5.3 mmol) in THF (50 mL) were added NaH (60%, 0.423 g, 10.6mmol). The mixture was stirred at room temperature for 30 minutes, andbenzyl bromide (1.085 g, 6.3 mmol) and TBAI (0.195 g, 0.5 mmol) wereadded. The mixture was stirred at room temperature for 12 hours, andquenched by addition of sat. NH₄Cl solution (20 mL). Concentrated invacuo, and the residue was taken up in water and EtOAc. The organiclayer was separated, and the aqueous phase was extracted with EtOAc.Combined organic phases were washed with water and brine, and dried(MgSO₄). The organic solvent was removed in vacuo to give the crudeproduct, which was purified by flash chromatography in silica gel withEtOAc:Hex (10:90) to give (2R′,3S′,5R′)-tert-butyl3-(benzyloxy)-2,5-bis((tert-butyldimethylsilyloxy)methyl)pyrrolidine-1-carboxylate(3.0 g, 100%) as colorless oil.

Step 6: Synthesis of (2R′,3S′,5R′)-tert-butyl3-(benzyloxy)-2,5-bis(hydroxymethyl)pyrrolidine-1-carboxylate (benzyloxydiol)

To a solution of (2R′,3S′,5R′)-tert-butyl3-(benzyloxy)-2,5-bis((tert-butyldimethylsilyloxy)methyl)pyrrolidine-1-carboxylate(3.0 g, 5.3 mmol) in THF (50 mL) was added slowly of TBAF solution (1 Min THF, 21.8 mL, 21.8 mmol) at 0° C. The resulting mixture was stirredat room temperature for 6, and quenched by addition of sat. NH₄Clsolution (10 mL). Concentrated in vacuo, and the residue was treatedwith water and EtOAc. The organic layer was separated, and the aqueousphase was extracted with EtOAc. Combined organic phases were washed withwater and brine, and dried (MgSO₄). The organic solvent was removed invacuo to give the crude product, which was purified by flashchromatography in silica gel with EtOAc:Hex:MeOH (50:50:5) to give thetitle compound (1.15 g, 62.5%).

Step 7: Synthesis of (6S′)-tert-butyl6-(benzyloxy)-3-oxa-8-azabicyclo[3.2.1]octane-8-carboxylate bycyclization

To a solution of (2R′,3S′,5R′)-tert-butyl3-(benzyloxy)-2,5-bis(hydroxymethyl)pyrrolidine-1-carboxylate (1.15 g,3.4 mmol) in THF (50 mL) was added NaH (60%, 0.409 g, 10.2 mmol). Themixture was stirred at room temperature for 30 minutes, and cooled downto 0° C. A solution of p-TsCl (0.65 g, 3.4 mmol) in THF (5 mL) wasslowly added to the mixture. The reaction mixture was then stirred atroom temperature for 12 hours, and quenched by addition of sat. NH₄Clsolution (20 mL). Concentrated in vacuo, and the residue was taken up inwater and EtOAc. The organic layer was separated, and the aqueous phasewas extracted with EtOAc. Combined organic phases were washed with waterand brine, and dried (MgSO₄). The organic solvent was removed in vacuoto give the crude product, which was purified by flash chromatography insilica gel with EtOAc:Hex (20:80) to give the title compound (716 mg,66%) as off-white solid.

The compounds in Table I were made by the proceeding methods.

TABLE ! MS (ESI) Example Name m/z 4781-(4-{[4-(dimethylamino)piperidin-1- 615.5yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2- yl]phenyl}urea 4791-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-3-(4- 589.6{4-morpholin-4-yl-6-[(3S)-tetrahydrofuran-3-yloxy]-1,3,5-triazin-2-yl}phenyl)urea 4801-{4-[4-(5-hydroxy-3-oxa-7-azabicyclo[4.1.1]oct-7-yl)- 505.3 253.26-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin- 273.8 4-ylurea481 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3- 464.2 253.1pyridazin-4-ylurea 4821-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-3-{4- 575.5[4-morpholin-4-yl-6-(oxetan-3-yloxy)-1,3,5-triazin-2- yl]phenyl}urea 4831-{4-[4-morpholin-4-yl-6-(3-oxa-8- 490.6azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridazin-4-ylurea 484 1-(4-{[(3R)-3-(dimethylamino)pyrrolidin-1- 602.5yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea 485 1-(4-{[(3S)-3-(dimethylamino)pyrrolidin-1-602.6 yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea 4861-[4-(4-isopropyl-6-morpholin-4-yl-1,3,5-triazin-2- 545.1 293.5yl)phenyl]-3-{4-[(4-methylpiperazin-1- 273 yl)carbonyl]phenyl}urea 4871-{4-[4-(1-methylethyl)-6-morpholin-4-yl-1,3,5-triazin- 497.32-yl]phenyl}-3-(4-pyrimidin-5-ylphenyl)urea 4881-(4-{4-[(2,2-dimethoxyethyl)amino]-6-morpholin-4- 481.2 241.1yl-1,3,5-triazin-2-yl}phenyl)-3-pyridin-3-ylurea 261.6 4891-{4-[4-(1-methylethyl)-6-morpholin-4-yl-1,3,5-triazin- 496.3 248.62-yl]phenyl}-3-(4-pyridin-4-ylphenyl)urea 269.1 4901-(4-iodophenyl)-3-{4-[4-(1-methylethyl)-6-morpholin- 545.14-yl-1,3,5-triazin-2-yl]phenyl}urea 4911-{4-[4-(1-methylethyl)-6-morpholin-4-yl-1,3,5-triazin- 573.4 287.22-yl]phenyl}-3-(4-{[4-(1-methylethyl)piperazin-1-yl]carbonyl}phenyl)urea 4921-[4-(4-azetidin-1-yl-6-morpholin-4-yl-1,3,5-triazin-2- 586.6yl)phenyl]-3-(4-{[4-(1-methylethyl)piperazin-1- yl]carbonyl}phenyl)urea493 1-{4-[2-(dimethylamino)pyrimidin-5-yl]phenyl}-3-{4-[4- 540.5(1-methylethyl)-6-morpholin-4-yl-1,3,5-triazin-2- yl]phenyl}urea 494tert-butyl 3-[(4-morpholin-4-yl-6-{4-[(pyridin-4- 549.6ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl)oxy]azetidine-1-carboxylate 495 1-(4-{[4-(dimethylamino)piperidin-1-616.4 308.7 yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea 4961-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3- 507.1(4-nitrophenyl)urea 4971-(4-aminophenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5- 477.1 259.6triazin-2-yl)phenyl]urea 498N-[4-({[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2- 603.2 302.1yl)phenyl]carbamoyl}amino)phenyl]-4- 322.6methylpiperazine-1-carboxamide 4994-(dimethylamino)-N-[4-({[4-(4,6-dimorpholin-4-yl- 631.31,3,5-triazin-2- yl)phenyl]carbamoyl}amino)phenyl]piperidine-1-carboxamide 500 1-[2-(dimethylamino)ethyl]-3-[4-({[4-(4,6-dimorpholin-605.3 4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)phenyl]-1-methylurea 5011-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3- 631.3(4-{[(2-piperidin-1- ylethyl)carbamoyl]amino}phenyl)urea 502N-[4-({[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2- 617.3yl)phenyl]carbamoyl}amino)phenyl]-4-methyl-1,4- diazepane-1-carboxamide503 N-[4-({[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2- 617.3yl)phenyl]carbamoyl}amino)phenyl]-4- ethylpiperazine-1-carboxamide 5041-{4-[(dimethylcarbamoyl)amino]phenyl}-3-[4-(4,6- 548.3dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea 5051-{4-[4-(3,6-dihydro-2H-pyran-4-yl)-6-morpholin-4-yl- 613.41,3,5-triazin-2-yl]phenyl}-3-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)urea 5064-[({4-[4-(3,6-dihydro-2H-pyran-4-yl)-6-morpholin-4- 587.4yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]-N-[2-(dimethylamino)ethyl]-N-methylbenzamide 5071-{4-[4-(3,6-dihydro-2H-pyran-4-yl)-6-morpholin-4-yl- 585.31,3,5-triazin-2-yl]phenyl}-3-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}urea 5084-[({4-[4-(3,6-dihydro-2H-pyran-4-yl)-6-morpholin-4- 573.3yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]-N-[2-(dimethylamino)ethyl]benzamide 509N-[4-({[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-yl- 668.41,3,5-triazin-2-yl)phenyl]carbamoyl}amino)phenyl]-2-(4-methylpiperazin-1-yl)acetamide 5101-(4-{[4-(dimethylamino)piperidin-1- 615.5yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2- yl]phenyl}urea 5111-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-3-{4- 587.3[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl]phenyl}urea 512N-[2-(dimethylamino)ethyl]-4-[({4-[4-morpholin-4-yl-6- 575.3(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide 5134-[({4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yl)- 601.31,3,5-triazin-2-yl]phenyl}carbamoyl)amino]-N-(2-pyrrolidin-1-ylethyl)benzamide 5144-[({4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yl)- 615.31,3,5-triazin-2-yl]phenyl}carbamoyl)amino]-N-(2-piperidin-1-ylethyl)benzamide 5151-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3- 616.3 308.6(4-{[4-(1-methylethyl)piperazin-1- 329.2 yl]carbonyl}phenyl)urea 5161-(4-{[(3S)-3-(dimethylamino)pyrrolidin-1- 627.7yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2- yl]phenyl}urea 5171-(4-{[(3S)-3-(dimethylamino)pyrrolidin-1- 449.4yl]carbonyl}phenyl)-3-{4-[4-morpholin- 5184-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5- 616.4triazin-2-yl]phenyl}urea 519N-[2-(dimethylamino)ethyl]-N-methyl-4-{[(4-{4- 616.4morpholin-4-yl-6-[(3S)-tetrahydrofuran-3-yloxy]-1,3,5-triazin-2-yl}phenyl)carbamoyl]amino}benzamide 5204-{[(4-{4-morpholin-4-yl-6-[(3S)-tetrahydrofuran-3- 616.4yloxy]-1,3,5-triazin-2-yl}phenyl)carbamoyl]amino}-N-(2-piperidin-1-ylethyl)benzamide 5214-{[(4-{4-morpholin-4-yl-6-[(3S)-tetrahydrofuran-3- 616.4yloxy]-1,3,5-triazin-2-yl}phenyl)carbamoyl]amino}-N-(2-pyrrolidin-1-ylethyl)benzamide 5221-(4-{[4-(1-methylethyl)piperazin-1- 616.4yl]carbonyl}phenyl)-3-(4-{4-morpholin-4-yl-6-[(3S)-tetrahydrofuran-3-yloxy]-1,3,5-triazin-2- yl}phenyl)urea 5231-(4-{[4-(1-methylethyl)piperazin-1- 616.4yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2- yl]phenyl}urea 524N-[2-(dimethylamino)ethyl]-N-methyl-4-[({4-[4- 616.4morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide 5254-[({4-[4-(2-methylpropyl)-6-morpholin-4-yl-1,3,5- 477.3triazin-2-yl]phenyl}carbamoyl)amino]benzoic acid 5261-{4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5- 565.4triazin-2-yl]phenyl}-3-[4-(4-methylpiperazin-1- yl)phenyl]urea 5274-[({4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5- 511.4triazin-2-yl]phenyl}carbamoyl)amino]benzoic acid 528 methyl4-[({4-[4-(4-methylphenyl)-6-morpholin-4-yl- 525.41,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzoate 5291-{4-[4-(dimethylamino)piperidin-1-yl]phenyl}-3-[4-(4- 531.4ethyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea 5301-{4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5- 468.3triazin-2-yl]phenyl}-3-pyridin-4-ylurea 5311-{4-[4-(dimethylamino)piperidin-1-yl]phenyl}-3-{4-[4- 593.4(4-methylphenyl)-6-morpholin-4-yl-1,3,5-triazin-2- yl]phenyl}urea 532N-[2-(dimethylamino)ethyl]-N-methyl-4-[({4-[4-(4- 595.5methylphenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide 5331-{4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5- 593.5triazin-2-yl]phenyl}-3-{4-[(4-methylpiperazin-1- yl)carbonyl]phenyl}urea534 1-[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2- 594.5yl)phenyl]-3-{4-[(4-pyridin-2-ylpiperazin-1- yl)carbonyl]phenyl}urea 5351-{4-[4-(dimethylamino)piperidin-1-yl]phenyl}-3-[4-(4- 579.5morpholin-4-yl-6-phenyl-1,3,5-triazin-2- yl)phenyl]urea 5361-[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2- 531.1yl)phenyl]-3-{4-[(4-methylpiperazin-1- yl)carbonyl]phenyl}urea 5371-[4-(4-morpholin-4-yl-6-phenyl-1,3,5-triazin-2- 454.1yl)phenyl]-3-pyridin-4-ylurea 538 methyl4-({[4-(4-morpholin-4-yl-6-phenyl-1,3,5- 511triazin-2-yl)phenyl]carbamoyl}amino)benzoate 539N-[2-(dimethylamino)ethyl]-N-methyl-4-({[4-(4- 581.2morpholin-4-yl-6-phenyl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzamide 540 methyl4-{[(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]- 5481,3,5-triazin-2-yl}phenyl)carbamoyl]amino}benzoate 5414-({[4-(4-morpholin-4-yl-6-phenyl-1,3,5-triazin-2- 497yl)phenyl]carbamoyl}amino)benzoic acid 542N-[2-(dimethylamino)ethyl]-4-[({4-[4-(4- 581.3methylphenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide 5431-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-3-[4- 579.2(4-morpholin-4-yl-6-phenyl-1,3,5-triazin-2- yl)phenyl]urea 5441-(4-{[4-(dimethylamino)piperidin-1- 661.5yl]carbonyl}phenyl)-3-[4-(4-morpholin-4-yl-6-phenyl-1,3,5-triazin-2-yl)phenyl]urea 545N-[2-(dimethylamino)ethyl]-4-({[4-(4-morpholin-4-yl- 567.26-phenyl-1,3,5-triazin-2- yl)phenyl]carbamoyl}amino)benzamide 5464-{[(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5- 604.4triazin-2-yl}phenyl)carbamoyl]amino}-N-[2-(dimethylamino)ethyl]benzamide 5471-{4-[(4-isopropylpiperazin-1-yl)carbonyl]phenyl}-3- 621.5{4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5-triazin- 2-yl]phenyl}urea548 4-[({4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5- 607.5triazin-2-yl]phenyl}carbamoyl)amino]-N-(2-pyrrolidin-1-ylethyl)benzamide 5494-{[(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5- 534.5triazin-2-yl}phenyl)carbamoyl]amino}benzoic acid 550N-(2-methoxyethyl)-4-[({4-[4-(4-methylphenyl)-6- 568.2morpholin-4-yl-1,3,5-triazin-2- yl]phenyl}carbamoyl)amino]benzamide 551N-(2-methoxyethyl)-4-({[4-(4-morpholin-4-yl-6- 554.2phenyl-1,3,5-triazin-2- yl)phenyl]carbamoyl}amino)benzamide 5524-({[4-(4-morpholin-4-yl-6-phenyl-1,3,5-triazin-2- 593.5yl)phenyl]carbamoyl}amino)-N-(2-pyrrolidin-1- ylethyl)benzamide 5531-{4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5- 567.6triazin-2-yl]phenyl}-3-[4-(pyrrolidin-1- ylcarbonyl)phenyl]urea 554N-[3-(dimethylamino)propyl]-4-[({4-[4-(4- 595.4methylphenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide 5551-{4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5- 578.1triazin-2-yl]phenyl}-3-[4-(piperidin-1- ylcarbonyl)phenyl]urea 556N-[3-(dimethylamino)propyl]-4-({[4-(4-morpholin-4-yl- 581.4 291.26-phenyl-1,3,5-triazin-2- yl)phenyl]carbamoyl}amino)benzamide 5571-{4-[4-morpholin-4-yl-6-(2-thienyl)-1,3,5-triazin-2- 460.2 230.6yl]phenyl}-3-pyridin-4-ylurea 5584-[({4-[4-morpholin-4-yl-6-(2-thienyl)-1,3,5-triazin-2- 503.4yl]phenyl}carbamoyl)amino]benzoic acid 5591-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-3-{4- 585.5[4-morpholin-4-yl-6-(2-thienyl)-1,3,5-triazin-2- yl]phenyl}urea 560methyl 4-[({4-[4-morpholin-4-yl-6-(2-thienyl)-1,3,5- 517.2triazin-2-yl]phenyl}carbamoyl)amino]benzoate 561N-(2-methoxyethyl)-4-[({4-[4-morpholin-4-yl-6-(2- 560.3thienyl)-1,3,5-triazin-2- yl]phenyl}carbamoyl)amino]benzamide 562N-[2-(dimethylamino)ethyl]-N-methyl-4-[({4-[4- 587.3 294.1morpholin-4-yl-6-(2-thienyl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide 563N-[2-(dimethylamino)ethyl]-4-[({4-[4-morpholin-4-yl-6- 573.1(2-thienyl)-1,3,5-triazin-2- yl]phenyl}carbamoyl)amino]benzamide 5644-{[(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5- 618.4 309.7triazin-2-yl}phenyl)carbamoyl]amino}-N-[2-(dimethylamino)ethyl]-N-methylbenzamide 5651-(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5- 616.4 329.2triazin-2-yl}phenyl)-3-{4-[(4-methylpiperazin-1- 308.7yl)carbonyl]phenyl}urea 5661-{4-[4-morpholin-4-yl-6-(1,4-oxazepan-4-yl)-1,3,5- 477.2triazin-2-yl]phenyl}-3-pyridin-4-ylurea 567 methyl4-[({4-[4-morpholin-4-yl-6-(1,4-oxazepan-4- 534.4 yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzoate 5681-(4-{[4-(dimethylamino)piperidin-1- 613.4 307.2yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6-(2-thienyl)-1,3,5-triazin-2-yl]phenyl}urea 5694-[({4-[4-morpholin-4-yl-6-(1,4-oxazepan-4-yl)-1,3,5- 520.3triazin-2-yl]phenyl}carbamoyl)amino]benzoic acid 570N-[3-(dimethylamino)propyl]-4-[({4-[4-morpholin-4-yl- 587.3 294.26-(2-thienyl)-1,3,5-triazin-2- yl]phenyl}carbamoyl)amino]benzamide 5711-(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5- 587.5triazin-2-yl}phenyl)-3-[4-(pyrrolidin-1- ylcarbonyl)phenyl]urea 572N-[2-(dimethylamino)ethyl]-4-[({4-[4-morpholin-4-yl-6- 590.3 295.6(1,4-oxazepan-4-yl)-1,3,5-triazin-2- yl]phenyl}carbamoyl)amino]benzamide573 1-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-3-{4- 602.3 322.2[4-morpholin-4-yl-6-(1,4-oxazepan-4-yl)-1,3,5-triazin- 301.72-yl]phenyl}urea 574 N-(2-methoxyethyl)-4-[({4-[4-morpholin-4-yl-6-(1,4-577.2 oxazepan-4-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide 5751-{4-[(4-ethylpiperazin-1-yl)carbonyl]phenyl}-3-{4-[4- 599.3 300.2morpholin-4-yl-6-(2-thienyl)-1,3,5-triazin-2- 320.7 yl]phenyl}urea 5761-{4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5- 593.3 317.7triazin-2-yl]phenyl}-3-{3-[(4-methylpiperazin-1- 521.3yl)carbonyl]phenyl}urea 5773-[({4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5- 511.2triazin-2-yl]phenyl}carbamoyl)amino]benzoic acid 578 methyl3-[({4-[4-(4-methylphenyl)-6-morpholin-4-yl- 525.21,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzoate 5791-(3-{[4-(dimethylamino)piperidin-1- 521.3yl]carbonyl}phenyl)-3-{4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}urea 580N-[2-(dimethylamino)ethyl]-N-methyl-3-[({4-[4-(4- 595.3 298.2methylphenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide 581 methyl3-({[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin- 463.52-yl)phenyl]carbamoyl}amino)benzoate 582 methyl3-({[4-(4-morpholin-4-yl-6-thiophen-2-yl-1,3,5- 517.2triazin-2-yl)phenyl]carbamoyl}amino)benzoate 583N-[2-(dimethylamino)ethyl]-3-[({4-[4-(4- 581.3 291.1methylphenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide 584N-[2-(dimethylamino)ethyl]-N-methyl-4-[({4-[4- 604.4 302.7morpholin-4-yl-6-(1,4-oxazepan-4-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide 5853-({[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2- 449.4yl)phenyl]carbamoyl}amino)benzoic acid 586 methyl3-({[4-(4-morpholin-4-yl-6-phenyl-1,3,5- 511.4triazin-2-yl)phenyl]carbamoyl}amino)benzoate 5871-[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2- 594.6yl)phenyl]-3-{3-[(4-pyridin-2-ylpiperazin-1- yl)carbonyl]phenyl}urea 588N-[2-(dimethylamino)ethyl]-3-({[4-(4-ethyl-6- 533.3 267.1morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)-N-methylbenzamide 5891-[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2- 531.3 266.1yl)phenyl]-3-{3-[(4-methylpiperazin-1- 286.7 yl)carbonyl]phenyl}urea 5903-({[4-(4-morpholin-4-yl-6-phenyl-1,3,5-triazin-2- 497.3yl)phenyl]carbamoyl}amino)benzoic acid 591 methyl4-({[4-(4-morpholin-4-yl-6-piperidin-1-yl-1,3,5- 518.3triazin-2-yl)phenyl]carbamoyl}amino)benzoate 5921-[4-(4-morpholin-4-yl-6-piperidin-1-yl-1,3,5-triazin-2- 461.3yl)phenyl]-3-pyridin-4-ylurea 5934-({[4-(4-morpholin-4-yl-6-piperidin-1-yl-1,3,5-triazin- 504..32-yl)phenyl]carbamoyl}amino)benzoic acid 594 methyl4-({[4-(4-morpholin-4-yl-6-pyrrolidin-1-yl- 504.51,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzoate 5951-(4-{[4-(1-methylethyl)piperazin-1- 604.5yl]carbonyl}phenyl)-3-[4-(4-morpholin-4-yl-6-piperidin-1-yl-1,3,5-triazin-2-yl)phenyl]urea 5961-{4-[(4-ethylpiperazin-1-yl)carbonyl]phenyl}-3-[4-(4- 600.5morpholin-4-yl-6-piperidin-1-yl-1,3,5-triazin-2- yl)phenyl]urea 5971-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-3-[4- 586.5(4-morpholin-4-yl-6-piperidin-1-yl-1,3,5-triazin-2- yl)phenyl]urea 5981-(4-{[4-(dimethylamino)piperidin-1- 614.5yl]carbonyl}phenyl)-3-[4-(4-morpholin-4-yl-6-piperidin-1-yl-1,3,5-triazin-2-yl)phenyl]urea 5994-({[4-(4-morpholin-4-yl-6-pyrrolidin-1-yl-1,3,5-triazin- 490.52-yl)phenyl]carbamoyl}amino)benzoic acid 6001-[4-(4-morpholin-4-yl-6-pyrrolidin-1-yl-1,3,5-triazin- 447.52-yl)phenyl]-3-pyridin-4-ylurea 601N-[2-(dimethylamino)ethyl]-4-({[4-(4-morpholin-4-yl- 474.66-piperidin-1-yl-1,3,5-triazin-2- yl)phenyl]carbamoyl}amino)benzamide602 1-(4-{[4-(dimethylamino)piperidin-1- 600.4 300.7yl]carbonyl}phenyl)-3-[4-(4-morpholin-4-yl-6-pyrrolidin-1-yl-1,3,5-triazin-2-yl)phenyl]urea 6031-(4-{[4-(1-methylethyl)piperazin-1- 600.4 300.7yl]carbonyl}phenyl)-3-[4-(4-morpholin-4-yl-6-pyrrolidin-1-yl-1,3,5-triazin-2-yl)phenyl]urea 604N-[2-(dimethylamino)ethyl]-N-methyl-4-({[4-(4- 574.6morpholin-4-yl-6-pyrrolidin-1-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzamide 605N-[2-(dimethylamino)ethyl]-N-methyl-4-({[4-(4- 588.3 294.6morpholin-4-yl-6-piperidin-1-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzamide 6061-{4-[(4-ethylpiperazin-1-yl)carbonyl]phenyl}-3-[4-(4- 586.3 293.7morpholin-4-yl-6-pyrrolidin-1-yl-1,3,5-triazin-2- 286.7 yl)phenyl]urea607 1-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-3-[4- 572.3(4-morpholin-4-yl-6-pyrrolidin-1-yl-1,3,5-triazin-2- yl)phenyl]urea 608N-[2-(dimethylamino)ethyl]-4-({[4-(4-morpholin-4-yl- 560.1 280.66-pyrrolidin-1-yl-1,3,5-triazin-2- yl)phenyl]carbamoyl}amino)benzamide609 1-(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5- 491.2 266.6triazin-2-yl}phenyl)-3-pyridin-4-ylurea 246.1 610N-[3-(dimethylamino)propyl]-4-({[4-(4-morpholin-4-yl- 588.3 294.66-piperidin-1-yl-1,3,5-triazin-2- yl)phenyl]carbamoyl}amino)benzamide611 N-(2-methoxyethyl)-4-({[4-(4-morpholin-4-yl-6- 561.4 281.2piperidin-1-yl-1,3,5-triazin-2- yl)phenyl]carbamoyl}amino)benzamide 6121-[4-(4-morpholin-4-yl-6-pyrrolidin-1-yl-1,3,5-triazin- 543.32-yl)phenyl]-3-[4-(pyrrolidin-1-ylcarbonyl)phenyl]urea 6131-(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5- 630.6triazin-2-yl}phenyl)-3-{4-[(4-ethylpiperazin-1- yl)carbonyl]phenyl}urea614 1-(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5- 644.7triazin-2-yl}phenyl)-3-(4-{[4-(1-methylethyl)piperazin-1-yl]carbonyl}phenyl)urea 615 methyl4-{[(4-{4-[(3S)-3-methylmorpholin-4-yl]-6- 534.3morpholin-4-yl-1,3,5-triazin-2- yl}phenyl)carbamoyl]amino}benzoate 6161-(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5- 644.6triazin-2-yl}phenyl)-3-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)urea 6171-(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-morpholin-4- 602.3 322.2yl-1,3,5-triazin-2-yl}phenyl)-3-{4-[(4-methylpiperazin- 301.71-yl)carbonyl]phenyl}urea 618 1-(4-{[4-(1-methylethyl)piperazin-1-630.4315.7 yl]carbonyl}phenyl)-3-(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)urea 6194-{[(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-morpholin- 520.24-yl-1,3,5-triazin-2- yl}phenyl)carbamoyl]amino}benzoic acid 6201-{4-[(4-ethylpiperazin-1-yl)carbonyl]phenyl}-3-(4-{4- 616.4 308.7[(3S)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5- 329.2triazin-2-yl}phenyl)urea 621N-[3-(dimethylamino)propyl]-4-{[(4-{4-[(3S)-3- 604.6methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)carbamoyl]amino}benzamide 6224-{[(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-morpholin- 616.54-yl-1,3,5-triazin-2-yl}phenyl)carbamoyl]amino}-N-(2-pyrrolidin-1-ylethyl)benzamide 6231-(4-{4-[(3R)-3-methylmorpholin-4-yl]-6-[(3S)-3- 616.4 308.7methylmorpholin-4-yl]-1,3,5-triazin-2-yl}phenyl)-3-{4- 329.2[(4-methylpiperazin-1-yl)carbonyl]phenyl}urea 6241-(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5- 700.6 350.8triazin-2-yl}phenyl)-3-(4-{[4-(dipropylamino)piperidin-1-yl]carbonyl}phenyl)urea 6251-{4-[(4-ethylpiperazin-1-yl)carbonyl]phenyl}-3-(4-{4- 630.5 315.7[(3R)-3-methylmorpholin-4-yl]-6-[(3S)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl}phenyl)urea 6264-{[(4-{4-[(3R)-3-methylmorpholin-4-yl]-6-[(3S)-3- 534.3methylmorpholin-4-yl]-1,3,5-triazin-2- yl}phenyl)carbamoyl]amino}benzoicacid 627 1-{4-[(4-butylpiperazin-1-yl)carbonyl]phenyl}-3-(4-{4- 658.6[(3R)-3-methylmorpholin-4-yl]-6-[(3S)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl}phenyl)urea 628 methyl4-{[(4-{4-[(3R)-3-methylmorpholin-4-yl]-6- 548.2[(3S)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl}phenyl)carbamoyl]amino}benzoate 6291-(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5- 658.5 329.7triazin-2-yl}phenyl)-3-{4-[(4-butylpiperazin-1- yl)carbonyl]phenyl}urea630 1-(4-{[4-(1-methylethyl)piperazin-1- 644.5yl]carbonyl}phenyl)-3-(4-{4-[(3R)-3-methylmorpholin-4-yl]-6-[(3S)-3-methylmorpholin-4-yl]-1,3,5-triazin-2- yl}phenyl)urea631 1-(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5- 658.5triazin-2-yl}phenyl)-3-(4-{[4-(2-methylpropyl)piperazin-1-yl]carbonyl}phenyl)urea 6321-(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5- 658.6triazin-2-yl}phenyl)-3-(4-{[4-(1-methylpropyl)piperazin-1-yl]carbonyl}phenyl)urea 6334-{[(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5- 659.6triazin-2-yl}phenyl)carbamoyl]amino}-N-[2-(4-methylpiperazin-1-yl)ethyl]benzamide 634N-[2-(dimethylamino)ethyl]-4-{[(4-{4-[(3R)-3- 604.5methylmorpholin-4-yl]-6-[(3S)-3-methylmorpholin-4- yl]-1,3,5-triazin-2-yl}phenyl)carbamoyl]amino}benzamide 6354-{[(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5- 626.5triazin-2-yl}phenyl)carbamoyl]amino}-N-(2-pyrrolidin-1-ylethyl)benzamide 6361-(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5- 643.4 322.2triazin-2-yl}phenyl)-3-{4-[(4-propylpiperidin-1- yl)carbonyl]phenyl}urea637 1-(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5- 601.5triazin-2-yl}phenyl)-3-[4-(piperidin-1- ylcarbonyl)phenyl]urea 6381-(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5- 643.5triazin-2-yl}phenyl)-3-{4-[(4-propylpiperazin-1- yl)carbonyl]phenyl}urea639 4-{[(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5- 591.6triazin-2-yl}phenyl)carbamoyl]amino}-N-(2- methoxyethyl)benzamide 6401-{4-[4-morpholin-4-yl-6-(4-tricyclo[3.3.1.13,7]dec-1- 596.7ylpiperazin-1-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4- ylurea 641methyl 4-{[(4-{4-[4-(dimethylcarbamoyl)piperazin-1- 590.5yl]-6-morpholin-4-yl-1,3,5-triazin-2- yl}phenyl)carbamoyl]amino}benzoate642 N,N-dimethyl-4-(4-morpholin-4-yl-6-{4-[(pyridin-4- 533.6ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2- yl)piperazine-1-carboxamide643 N,N-dimethyl-4-(4-{4-[({4-[(4-methylpiperazin-1- 658.3 329.7yl)carbonyl]phenyl}carbamoyl)amino]phenyl}-6-morpholin-4-yl-1,3,5-triazin-2-yl)piperazine-1- carboxamide 644N,N-dimethyl-4-{4-morpholin-4-yl-6-[4-({[4-(pyridazin- 653.34-ylcarbamoyl)phenyl]carbamoyl}amino)phenyl]-1,3,5-triazin-2-yl}piperazine-1-carboxamide 645N,N-dimethyl-4-(4-morpholin-4-yl-6-{4-[({4-[(4- 685.6 propylpiperidin-1-yl)carbonyl]phenyl}carbamoyl)amino]phenyl}-1,3,5-triazin-2-yl)piperazine-1-carboxamide 6464-{[(4-{4-[4-(dimethylcarbamoyl)piperazin-1-yl]-6- 576.2morpholin-4-yl-1,3,5-triazin-2- yl}phenyl)carbamoyl]amino}benzoic acid647 4-(4-{4-[({4-[(2- 633.3 317.1methoxyethyl)carbamoyl]phenyl}carbamoyl)amino]phenyl}-6-morpholin-4-yl-1,3,5-triazin-2-yl)-N,N-dimethylpiperazine-1-carboxamide 648 4-[4-(4-{[(4-{[2- 660.3 330.7(dimethylamino)ethyl](methyl)carbamoyl}phenyl)carbamoyl]amino}phenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]-N,N-dimethylpiperazine-1-carboxamide 6494-(4-{4-[({4-[(4-ethylpiperazin-1- 672.6yl)carbonyl]phenyl}carbamoyl)amino]phenyl}-6-morpholin-4-yl-1,3,5-triazin-2-yl)-N,N- dimethylpiperazine-1-carboxamide650 1-(4-{4-[4-(ethylsulfonyl)piperazin-1-yl]-6-morpholin- 554.24-yl-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea 651 methyl4-{[(4-{4-[4-(ethylsulfonyl)piperazin-1-yl]-6- 611.2morpholin-4-yl-1,3,5-triazin-2- yl}phenyl)carbamoyl]amino}benzoate 6524-{[(4-{4-[4-(ethylsulfonyl)piperazin-1-yl]-6-morpholin- 597.74-yl-1,3,5-triazin-2- yl}phenyl)carbamoyl]amino}benzoic acid 653N-[3-(dimethylamino)propyl]-4-{[(4-{4-[4- 681.2 341.1(ethylsulfonyl)piperazin-1-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)carbamoyl]amino}benzamide 654N-[2-(dimethylamino)ethyl]-4-{[(4-{4-[4- 667.3 334.2(ethylsulfonyl)piperazin-1-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)carbamoyl]amino}benzamide 6554-{[(4-{4-[4-(1-methylethyl)-1,4-diazepan-1-yl]-6- 561.5morpholin-4-yl-1,3,5-triazin-2- yl}phenyl)carbamoyl]amino}benzoic acid656 methyl 4-{[(4-{4-[4-(acetylamino)piperidin-1-yl]-6- 575.4morpholin-4-yl-1,3,5-triazin-2- yl}phenyl)carbamoyl]amino}benzoate 6571-(4-{4-[4-(1-methylethyl)-1,4-diazepan-1-yl]-6- 643.6morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}urea 658N-[1-(4-morpholin-4-yl-6-{4-[(pyridin-4- 518.5ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2- yl)piperidin-4-yl]acetamide659 4-{[(4-{4-[4-(acetylamino)piperidin-1-yl]-6-morpholin- 561.54-yl-1,3,5-triazin-2- yl}phenyl)carbamoyl]amino}benzoic acid 660N-[2-(dimethylamino)ethyl]-4-{[(4-{4-[4-(1- 631.5methylethyl)-1,4-diazepan-1-yl]-6-morpholin-4-yl- 1,3,5-triazin-2-yl}phenyl)carbamoyl]amino}benzamide 661N-{1-[(4-{[(4-{4-[4-(1-methylethyl)-1,4-diazepan-1-yl]- 685.66-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)carbamoyl]amino}phenyl)carbonyl]piperidin- 4-yl}acetamide 6621-{4-[(4-ethylpiperazin-1-yl)carbonyl]phenyl}-3-(4-{4- 657.4 329.2[4-(1-methylethyl)-1,4-diazepan-1-yl]-6-morpholin-4- 219.8yl-1,3,5-triazin-2-yl}phenyl)urea 6631-(4-{4-[4-(1-methylethyl)-1,4-diazepan-1-yl]-6- 671.4 336.2morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-(4-{[4-(1- 224.5methylethyl)piperazin-1-yl]carbonyl}phenyl)urea 6641-(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5- 617.5triazin-2-yl}phenyl)-3-(4-{[(3S)-3-methylmorpholin-4-yl]carbonyl}phenyl)urea 6651-{4-[(4-butylpiperazin-1-yl)carbonyl]phenyl}-3-(4-{4- 685.6[4-(1-methylethyl)-1,4-diazepan-1-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)urea 666N-[4-({[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)phenyl]-2-(4-methylpiperazin-1-yl)acetamide 6671-(4-{4-[(2R,5S)-2,5-bis(hydroxymethyl)pyrrolidin-1- 533.3yl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea 6681-(4-{4-[(2R,5S)-2,5-bis(hydroxymethyl)pyrrolidin-1- 630.4yl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-[4-(4-methylpiperazin-1-yl)phenyl]urea 6691-{4-[4-morpholin-4-yl-6-(3-oxa-8- 489.3azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea 670 4-[({4-[4-morpholin-4-yl-6-(3-oxa-8- 531.2azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide 6711-{4-[4-morpholin-4-yl-6-(3-oxa-8- 489.5azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea 6721-(4-fluorophenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8- 506.5azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2- yl]phenyl}urea 6731-[4-(hydroxymethyl)phenyl]-3-{4-[4-morpholin-4-yl- 518.56-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2- yl]phenyl}urea674 1-[4-(2-hydroxyethyl)phenyl]-3-{4-[4-morpholin-4-yl- 532.56-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2- yl]phenyl}urea675 2-(diethylamino)ethyl 4-[({4-[4-morpholin-4-yl-6-(3- 631.6oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzoate 6761-(4-methylphenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa- 502.58-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2- yl]phenyl}urea 6771-(4-cyanophenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8- 513.5azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2- yl]phenyl}urea 6781-[4-(4-methylpiperazin-1-yl)phenyl]-3-{4-[4- 586.6morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea 6791-isopropyl-3-{4-[4-morpholin-4-yl-6-(3-oxa-8- 454.5azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2- yl]phenyl}urea 6801-(2-hydroxyethyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8- 456.5azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2- yl]phenyl}urea 6814-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct- 369.28-yl)-1,3,5-triazin-2-yl]aniline 682{3-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct- 384.48-yl)-1,3,5-triazin-2-yl]phenyl}methanol 6833-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct- 370.48-yl)-1,3,5-triazin-2-yl]phenol 6845-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct- 409.48-yl)-1,3,5-triazin-2-yl]-1H-benzimidazol-2-amine 6851-{4-[4-(3-hydroxy-8-azabicyclo[3.2.1]oct-8-yl)-6- 502.5morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3- phenylurea 6861-(4-{4-[(4-methylpiperazin-1-yl)amino]-6-morpholin- 490.54-yl-1,3,5-triazin-2-yl}phenyl)-3-phenylurea 6871-(4-{4-[(1-methylpiperidin-4-yl)oxy]-6-morpholin-4- 491.5yl-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea 6881-{4-[4-morpholin-4-yl-6-(piperidin-4-yloxy)-1,3,5- 477.5triazin-2-yl]phenyl}-3-pyridin-4-ylurea 689 ethyl4-[(4-morpholin-4-yl-6-{4-[(pyridin-4- 549.5ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl)oxy]piperidine-1-carboxylate 690N-ethyl-4-[(4-morpholin-4-yl-6-{4-[(pyridin-4- 548.5ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl)oxy]piperidine-1-carboxamide 691 tert-butyl4-[(4-morpholin-4-yl-6-{4-[(pyridin-4- 577.3ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl)oxy]piperidine-1-carboxylate 6924-[(4-morpholin-4-yl-6-{4-[(pyridin-4- 556.5ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl)oxy]piperidine-1-sulfonamide 693 methyl4-[({4-[4-morpholin-4-yl-6-(3-oxa-8- 546.3azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzoate 694N-[2-(dimethylamino)ethyl]-4-[({4-[4-morpholin-4-yl-6- 602.4(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide 695N,N-dimethyl-4-[({4-[4-morpholin-4-yl-6-(3-oxa-8- 559.2azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide 696N-methyl-4-[({4-[4-morpholin-4-yl-6-(3-oxa-8- 545.2azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide 6971-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-3-{4- 614.3[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea 698N-[2-(dimethylamino)ethyl]-N-methyl-4-[({4-[4- 616.4morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)- 1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide 699N-(2-hydroxyethyl)-4-[({4-[4-morpholin-4-yl-6-(3-oxa- 575.48-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide 700N-[3-(dimethylamino)propyl]-4-[({4-[4-morpholin-4-yl- 616.46-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide 701N-methyl-N-[2-(methylamino)ethyl]-4-[({4-[4- 602.4morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)- 1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide 702N-(2-morpholin-4-ylethyl)-4-[({4-[4-morpholin-4-yl-6- 644.4(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide 7031-{4-[(3,5-dimethylpiperazin-1-yl)carbonyl]phenyl}-3- 628.4{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea 7044-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-6-morpholin- 399.34-yl-1,3,5-triazin-2-yl]aniline 7051-{4-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-6- 519.7morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4- ylurea 7061-{4-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-6- 519.2morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3- ylurea 7071-{4-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-6- 518.2morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3- phenylurea 7081-[4-(dimethylamino)phenyl]-3-{4-[4-(1,4-dioxa-8- 561.3azaspiro[4.5]dec-8-yl)-6-morpholin-4-yl-1,3,5-triazin- 2-yl]phenyl}urea709 1-(4-cyanophenyl)-3-{4-[4-(1,4-dioxa-8- 543.2azaspiro[4.5]dec-8-yl)-6-morpholin-4-yl-1,3,5-triazin- 2-yl]phenyl}urea710 1-{4-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-6- 533.7morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-(2- methylpyridin-4-yl)urea711 1-[2-(dimethylamino)ethyl]-3-{4-[4-(1,4-dioxa-8- 513.7azaspiro[4.5]dec-8-yl)-6-morpholin-4-yl-1,3,5-triazin- 2-yl]phenyl}urea712 1-[4-(4-morpholin-4-yl-6-quinolin-3-yl-1,3,5-triazin-2- 505.7yl)phenyl]-3-pyridin-4-ylurea 7131-(diethylcarbamoyl)-4-[({4-[4-morpholin-4-yl-6-(3- 588.3oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]pyridinium 7141-{4-[4-(2-methoxyethoxy)-6-morpholin-4-yl-1,3,5- 452.6triazin-2-yl]phenyl}-3-pyridin-4-ylurea 715 methyl4-[({4-[4-(2-methoxyethoxy)-6-morpholin-4-yl- 509.41,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzoate 7164-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-yl-1,3,5- 395.3triazin-2-yl)aniline 7171-[4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-yl-1,3,5- 515.8triazin-2-yl)phenyl]-3-pyridin-4-ylurea 7181-(4-{4-morpholin-4-yl-6-[2-(pyridin-4-ylamino)ethyl]- 498.61,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea 7191-(4-acetylphenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8- 530.4azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2- yl]phenyl}urea 720N-[2-(dimethylamino)ethyl]-4-({[4-(4-methoxy-6- 535.5morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)-N-methylbenzamide 721N-[2-(dimethylamino)ethyl]-4-({[4-(4-methoxy-6- 521.5morpholin-4-yl-1,3,5-triazin-2- yl)phenyl]carbamoyl}amino)benzamide 7224-({[4-(4-methoxy-6-morpholin-4-yl-1,3,5-triazin-2- 521.5yl)phenyl]carbamoyl}amino)-N-methyl-N-[2- (methylamino)ethyl]benzamide723 1-[4-(4-methoxy-6-morpholin-4-yl-1,3,5-triazin-2- 533.5yl)phenyl]-3-{4-[(4-methylpiperazin-1- yl)carbonyl]phenyl}urea 7241-{4-[(3,3-dimethylpiperazin-1-yl)carbonyl]phenyl}-3- 547.5[4-(4-methoxy-6-morpholin-4-yl-1,3,5-triazin-2- yl)phenyl]urea 7254-({[4-(4-methoxy-6-morpholin-4-yl-1,3,5-triazin-2- 561.5yl)phenyl]carbamoyl}amino)-N-(2-piperidin-1- ylethyl)benzamide 7261-(4-ethenylphenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa- 514.38-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2- yl]phenyl}urea 7271-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}-3-{4-[4- 601.1morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea 7281-(4-{4-[2,5-bis(hydroxymethyl)pyrrolidin-1-yl]-6- 508morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4- ylurea 7291-{4-[2-(dimethylamino)ethoxy]phenyl}-3-{4-[4- 575.5morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea 7301-(4-{4-[2-(1,3-dioxan-2-yl)ethyl]-6-morpholin-4-yl- 492.91,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea 7311-(4-{4-[3-(dimethylamino)propyl]-6-morpholin-4-yl- 463.41,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea 7321-[4-(4-{3-[(1-methylethyl)amino]propyl}-6-morpholin- 477.44-yl-1,3,5-triazin-2-yl)phenyl]-3-pyridin-4-ylurea 7331-{4-[4-morpholin-4-yl-6-(3-pyrrolidin-1-ylpropyl)- 489.41,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea 7341-(4-{4-[3-(4-methylpiperazin-1-yl)propyl]-6- 518.4morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4- ylurea 7351-{4-[4-(3-{[2-(dimethylamino)ethyl]amino}propyl)-6- 506.5morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4- ylurea 7361-{4-[4-(3-hydroxypropyl)-6-morpholin-4-yl-1,3,5- 436.3triazin-2-yl]phenyl}-3-pyridin-4-ylurea 7371-{4-[4-morpholin-4-yl-6-(3-oxopropyl)-1,3,5-triazin-2- 434.3yl]phenyl}-3-pyridin-4-ylurea 7384-[4-(6,8-dioxa-3-azabicyclo[3.2.1]oct-3-yl)-6- 371.3morpholin-4-yl-1,3,5-triazin-2-yl]aniline 739 tert-butyl7-[4-(4-aminophenyl)-6-morpholin-4-yl- 484.41,3,5-triazin-2-yl]-9-oxa-3,7- diazabicyclo[3.3.1]nonane-3-carboxylate740 1-{4-[4-(6,8-dioxa-3-azabicyclo[3.2.1]oct-3-yl)-6- 491.3morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4- ylurea 741tert-butyl 7-(4-morpholin-4-yl-6-{4-[(pyridin-4- 604.4ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate 7421-{4-[4-morpholin-4-yl-6-(9-oxa-3,7- 504.4diazabicyclo[3.3.1]non-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea 7431-{4-[4-(7-methyl-9-oxa-3,7-diazabicyclo[3.3.1]non-3- 518.4yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3- pyridin-4-ylurea 7441-{4-[4-(7-acetyl-9-oxa-3,7-diazabicyclo[3.3.1]non-3- 546.4yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3- pyridin-4-ylurea 7451-(4-{4-[7-(methylsulfonyl)-9-oxa-3,7- 582.5diazabicyclo[3.3.1]non-3-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea 7461-(2-chloropyridin-4-yl)-3-{4-[4-morpholin-4-yl-6-(3- 523.3oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2- yl]phenyl}urea 7471-(2,3′-bipyridin-4-yl)-3-{4-[4-morpholin-4-yl-6-(3-oxa- 566.48-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2- yl]phenyl}urea 748tert-butyl N-[4-morpholin-4-yl-6-(4-nitrophenyl)-1,3,5- 417.2triazin-2-yl]glycinate 7491-(6-chloropyridin-3-yl)-3-{4-[4-morpholin-4-yl-6-(3- 523.3oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2- yl]phenyl}urea 750N-[4-morpholin-4-yl-6-(4-nitrophenyl)-1,3,5-triazin-2- 361.3 yl]glycine751 1,3-bis{4-[4-morpholin-4-yl-6-(3-oxa-8- 763.5azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2- yl]phenyl}urea 7521-(4-{[4-(dimethylamino)piperidin-1- 642.4yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2- yl]phenyl}urea 753N-[2-(4-methylpiperazin-1-yl)ethyl]-4-[({4-[4- 657.4morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)- 1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide 7541-{4-[(4-isopropylpiperazin-1-yl)carbonyl]phenyl}-3- 642.4{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea 7551-{4-[(4-cyclopentylpiperazin-1-yl)carbonyl]phenyl}-3- 668.4{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea 7561-{4-[4-morpholin-4-yl-6-(3-oxa-8- 600.4azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}-3-[4-(piperazin-1-ylcarbonyl)phenyl]urea 7571-{4-[4-morpholin-4-yl-6-(3-oxa-8- 684.4azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}-3-{4-[(4-morpholin-4-ylpiperidin-1- yl)carbonyl]phenyl}urea 7584-[({4-[4-morpholin-4-yl-6-(3-oxa-8- 628.4azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]-N-(2-pyrrolidin-1- ylethyl)benzamide 7594-[({4-[4-morpholin-4-yl-6-(3-oxa-8- 642.4azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]-N-(2-piperidin-1- ylethyl)benzamide 7601-[4-(1,4′-bipiperidin-1′-ylcarbonyl)phenyl]-3-{4-[4- 682.5morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea 761 1-{4-[4-morpholin-4-yl-6-(3-oxa-8-668.5 azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}-3-{4-[(4-pyrrolidin-1-ylpiperidin-1- yl)carbonyl]phenyl}urea 7621-{4-[4-morpholin-4-yl-6-(3-oxa-8- 617.3azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}-3-[4-(thiomorpholin-4-ylcarbonyl)phenyl]urea 7631-[4-(morpholin-4-ylcarbonyl)phenyl]-3-{4-[4- 601.4morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea 764 4-[({4-[4-morpholin-4-yl-6-(3-oxa-8-532.3 azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzoic acid 7651-{4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6- 505.3morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4- ylurea 7661-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-3-{4-[4- 587.4morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea 767 1-(4-{[4-(dimethylamino)piperidin-1-658.4 yl]carbonyl}phenyl)-3-{4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}urea 768N-[2-(dimethylamino)ethyl]-4-[({4-[4-(3,7-dioxa-9- 632.4azabicyclo[3.3.1]non-9-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]-N- methylbenzamide 7691-{4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6- 630.4morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}urea 770 methyl4-[({4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9- 562.3yl)-6-morpholin-4-yl-1,3,5-triazin-2- yl]phenyl}carbamoyl)amino]benzoate771 4-[({4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6- 548.3morpholin-4-yl-1,3,5-triazin-2- yl]phenyl}carbamoyl)amino]benzoic acid772 1-{4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6- 616.3morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-[4-(piperazin-1-ylcarbonyl)phenyl]urea 7731-{4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6- 658.3morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-{4-[(4-isopropylpiperazin-1-yl)carbonyl]phenyl}urea 7744-[({4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6- 644.3morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]-N-(2-pyrrolidin-1- ylethyl)benzamide 7754-[({4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6- 658.4morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]-N-(2-piperidin-1- ylethyl)benzamide 7761-{4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6- 684.4morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-{4-[(4-pyrrolidin-1-ylpiperidin-1-yl)carbonyl]phenyl}urea 7771-[4-(1,4′-bipiperidin-1′-ylcarbonyl)phenyl]-3-{4-[4- 698.4(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}urea 7784-[({4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6- 652.4morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]-N-(2-pyridin-2- ylethyl)benzamide 7794-[({4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6- 652.4morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]-N-(2-pyridin-4- ylethyl)benzamide 780N-[4-(4-aminophenyl)-6-morpholin-4-yl-1,3,5-triazin- 413.22-yl]benzenesulfonamide 781 N-(4-morpholin-4-yl-6-{4-[(pyridin-4- 533.4ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2- yl)benzenesulfonamide 782N-{4-[4-({[4-(4-methylpiperazin-1- 630.3yl)phenyl]carbamoyl}amino)phenyl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}benzenesulfonamide 783 N-(4-{4-[({4-[2- 619.3(dimethylamino)ethoxy]phenyl}carbamoyl)amino]phenyl}-6-morpholin-4-yl-1,3,5-triazin-2- yl)benzenesulfonamide 784N-(4-{4-[({4-[(4-methylpiperazin-1- 658.3yl)carbonyl]phenyl}carbamoyl)amino]phenyl}-6-morpholin-4-yl-1,3,5-triazin-2-yl)benzenesulfonamide 785N-{4-morpholin-4-yl-6-[4-({[4-(piperazin-1- 644.4ylcarbonyl)phenyl]carbamoyl}amino)phenyl]-1,3,5-triazin-2-yl}benzenesulfonamide 786N-[4-(4-{[(4-{[4-(dimethylamino)piperidin-1- 686.4yl]carbonyl}phenyl)carbamoyl]amino}phenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]benzenesulfonamide 787N-[2-(dimethylamino)ethyl]-N-methyl-4-{[(4-{4- 660.4morpholin-4-yl-6-[(phenylsulfonyl)amino]-1,3,5-triazin-2-yl}phenyl)carbamoyl]amino}benzamide 788N-[2-(dimethylamino)ethyl]-4-{[(4-{4-morpholin-4-yl- 646.46-[(phenylsulfonyl)amino]-1,3,5-triazin-2-yl}phenyl)carbamoyl]amino}benzamide 789 methyl4-{[(4-{4-morpholin-4-yl-6- 590.3[(phenylsulfonyl)amino]-1,3,5-triazin-2-yl}phenyl)carbamoyl]amino}benzoate 7904-{[(4-{4-morpholin-4-yl-6-[(phenylsulfonyl)amino]- 576.21,3,5-triazin-2-yl}phenyl)carbamoyl]amino}benzoic acid 7911-{4-[4-morpholin-4-yl-6-(3-oxa-9- 503.2azabicyclo[3.3.1]non-9-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea 7921-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-3-{4- 628.5[4-morpholin-4-yl-6-(3-oxa-9-azabicyclo[3.3.1]non-9-yl)-1,3,5-triazin-2-yl]phenyl}urea 7931-{4-[4-morpholin-4-yl-6-(3-oxa-9- 614.5azabicyclo[3.3.1]non-9-yl)-1,3,5-triazin-2-yl]phenyl}-3-[4-(piperazin-1-ylcarbonyl)phenyl]urea 7941-(4-{[4-(dimethylamino)piperidin-1- 656.5yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-9-azabicyclo[3.3.1]non-9-yl)-1,3,5-triazin-2- yl]phenyl}urea 795N-[2-(dimethylamino)ethyl]-N-methyl-4-[({4-[4- 630.4morpholin-4-yl-6-(3-oxa-9-azabicyclo[3.3.1]non-9-yl)- 1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide 796N-[2-(dimethylamino)ethyl]-4-[({4-[4-morpholin-4-yl-6- 616.4(3-oxa-9-azabicyclo[3.3.1]non-9-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide 797N-(2-methoxyethyl)-4-[({4-[4-morpholin-4-yl-6-(3-oxa- 603.49-azabicyclo[3.3.1]non-9-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide 7984-[({4-[4-morpholin-4-yl-6-(3-oxa-9- 642.4azabicyclo[3.3.1]non-9-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]-N-(2-pyrrolidin-1- ylethyl)benzamide 7994-[({4-[4-morpholin-4-yl-6-(3-oxa-9- 656.4azabicyclo[3.3.1]non-9-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]-N-(2-piperidin-1- ylethyl)benzamide 8001-{4-[4-morpholin-4-yl-6-(3-oxa-9- 682.5azabicyclo[3.3.1]non-9-yl)-1,3,5-triazin-2-yl]phenyl}-3-{4-[(4-pyrrolidin-1-ylpiperidin-1- yl)carbonyl]phenyl}urea 801N-[2-(1-methylpyrrolidin-2-yl)ethyl]-4-[({4-[4- 656.6morpholin-4-yl-6-(3-oxa-9-azabicyclo[3.3.1]non-9-yl)- 1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide 802N-methyl-N-[2-(methylamino)ethyl]-4-[({4-[4- 616.5morpholin-4-yl-6-(3-oxa-9-azabicyclo[3.3.1]non-9-yl)- 1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide 8031-{4-[(4-ethylpiperazin-1-yl)carbonyl]phenyl}-3-{4-[4- 628.3morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea 8041-{4-[(4-ethylpiperazin-1-yl)carbonyl]phenyl}-3-{4-[4- 642.5morpholin-4-yl-6-(3-oxa-9-azabicyclo[3.3.1]non-9-yl)-1,3,5-triazin-2-yl]phenyl}urea 805 1-(4-{[4-(1-methylethyl)piperazin-1-656.3 yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-9-azabicyclo[3.3.1]non-9-yl)-1,3,5-triazin-2- yl]phenyl}urea 8061-{4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6- 644.5morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-{4-[(4-ethylpiperazin-1-yl)carbonyl]phenyl}urea 8071-{4-[4-morpholin-4-yl-6-(2-oxa-5- 489.2azabicyclo[2.2.2]oct-5-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea 8081-(1,3-dimethyl-1H-pyrazol-5-yl)-3-{4-[4-morpholin-4- 506.2yl-6-(2-oxa-5-azabicyclo[2.2.2]oct-5-yl)-1,3,5-triazin- 2-yl]phenyl}urea809 1-{4-[4-morpholin-4-yl-6-(2-oxa-5- 478.2azabicyclo[2.2.2]oct-5-yl)-1,3,5-triazin-2-yl]phenyl}-3-(1H-pyrazol-3-yl)urea 810 1-(4-{[4-(dimethylamino)piperidin-1- 642.2yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6-(2-oxa-5-azabicyclo[2.2.2]oct-5-yl)-1,3,5-triazin-2- yl]phenyl}urea 8111-(4-{[4-(1-methylethyl)piperazin-1- 642.5yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6-(2-oxa-5-azabicyclo[2.2.2]oct-5-yl)-1,3,5-triazin-2- yl]phenyl}urea 8121-{4-[(4-ethylpiperazin-1-yl)carbonyl]phenyl}-3-{4-[4- 628.2morpholin-4-yl-6-(2-oxa-5-azabicyclo[2.2.2]oct-5-yl)-1,3,5-triazin-2-yl]phenyl}urea 8131-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-3-{4- 614.2[4-morpholin-4-yl-6-(2-oxa-5-azabicyclo[2.2.2]oct-5-yl)-1,3,5-triazin-2-yl]phenyl}urea 8141-{4-[4-morpholin-4-yl-6-(2-oxa-5- 600.3azabicyclo[2.2.2]oct-5-yl)-1,3,5-triazin-2-yl]phenyl}-3-[4-(piperazin-1-ylcarbonyl)phenyl]urea 815N-[2-(dimethylamino)ethyl]-4-[({4-[4-morpholin-4-yl-6- 602.5(2-oxa-5-azabicyclo[2.2.2]oct-5-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide 816N-[2-(dimethylamino)ethyl]-N-methyl-4-[({4-[4- 616.3morpholin-4-yl-6-(2-oxa-5-azabicyclo[2.2.2]oct-5-yl)- 1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide 8172-tert-butoxy-4-morpholin-4-yl-6-(4-nitrophenyl)- 360.1 1,3,5-triazine818 1-(4-{4-[(6S)-6-hydroxy-3-oxa-8-azabicyclo[3.2.1]oct- 505.28-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3- pyridin-4-ylurea819 1-(4-{4-[6-(benzyloxy)-3-oxa-8-azabicyclo[3.2.1]oct- 595.28-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3- pyridin-4-ylurea820 1-(4-{4-[(6R)-6-hydroxy-3-oxa-8-azabicyclo[3.2.1]oct- 505.28-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3- pyridin-4-ylurea821 1-(4-{4-[(6R)-6-(benzyloxy)-3-oxa-8- 595.2azabicyclo[3.2.1]oct-8-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea 8221-{4-[(1,1-dioxidothiomorpholin-4- 649.1yl)carbonyl]phenyl}-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2- yl]phenyl}urea 8231-[4-(4,6-di-3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl- 644.33061,3,5-triazin-2-yl)phenyl]-3-[4-(4-methylpiperazin-1- yl)phenyl]urea 8241-(4-{[(3S)-3-(dimethylamino)pyrrolidin-1- 628.5,yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa- 314.8, 356.88-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2- yl]phenyl}urea 8251-(4-{[(3R)-3-(dimethylamino)pyrrolidin-1- 628.5,yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa- 314.8, 356.88-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2- yl]phenyl}urea 8261-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-3-[4- 519.1,(6-morpholin-4-yl-4-oxo-4,5-dihydro-1,3,5-triazin-2- 280.5, 260yl)phenyl]urea 827 1-(4-{[(3S)-3-(dimethylamino)pyrrolidin-1- 628.5;yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa- 314.8;8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2- 356.8; yl]phenyl}urea 8281-(4-{[(3R)-3-(dimethylamino)pyrrolidin-1- 628.5;yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa- 314.8;8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2- 356.8; yl]phenyl}urea 8291-(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-(3-oxa-8- 503.4;azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl}phenyl)-3- 272.7;pyridin-4-ylurea 252.2; 8301-(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl}phenyl)-3-(4-{[4-(propan-2-yl)piperazin-1- yl]carbonyl}phenyl)urea 831N-[2-(dimethylamino)ethyl]-N-methyl-4-{[(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl}phenyl)carbamoyl]amino}benzamide 8324-{[(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-(3-oxa-8- 546.2;azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2- 568.2;yl}phenyl)carbamoyl]amino}benzoic acid 8331-(4-{[(3R)-3-(dimethylamino)pyrrolidin-1- 642.4;yl]carbonyl}phenyl)-3-(4-{4-[(3S)-3-methylmorpholin- 664.3;4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5- 680.3;triazin-2-yl}phenyl)urea 834 1-(4-{[(3S)-3-(dimethylamino)pyrrolidin-1-642.4; yl]carbonyl}phenyl)-3-(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl}phenyl)urea 8351-(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-(3-oxa-8- 628.3;azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl}phenyl)-3-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}urea 8361-{4-[(4-ethylpiperazin-1-yl)carbonyl]phenyl}-3-(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2- yl}phenyl)urea 8371-{4-[4-(morpholin-4-yl)-6-(3-oxa-8- 642.4; 664.3;azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}-3-{4-[(3,3,4-trimethylpiperazin-1- yl)carbonyl]phenyl}urea 8381-(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl}phenyl)-3-[4-(piperazin-1-ylcarbonyl)phenyl]urea

Biological Evaluation mTOR Kinase Assay Methods

Human mTOR assays (See Toral-Barza, et al. Biochem Biophys. Res. Commun.2005 June 24; 332(1):304-10) with purified enzyme are performed in96-well plates by DELFIA format as follows. Enzymes are first diluted inkinase assay buffer (10 mM HEPES (pH 7.4), 50 mM NaCl, 50 mMβ-glycerophosphate, 10 mM MnCl₂, 0.5 mM DTT, 0.25 mM microcystin LR, and100 mg/mL BSA). To each well, 12 μL of the diluted enzyme is mixedbriefly with 0.5 μL test inhibitor or control vehicle dimethylsulfoxide(DMSO). The kinase reaction is initiated by adding 12.5 μL kinase assaybuffer containing ATP and His6-S6K to give a final reaction volume of 25μL containing 800 ng/mL FLAG-TOR, 100 mM ATP and 1.25 mM His6-S6K. Thereaction plate is incubated for 2 hours (linear at 1-6 hours) at roomtemperature with gentle shaking and then terminated by adding 25 μL Stopbuffer (20 mM HEPES (pH 7.4), 20 mM EDTA, 20 mM EGTA). The DELFIAdetection of the phosphorylated (Thr-389) His6-S6K is performed at roomtemperature using a monoclonal anti-P(T389)-p70S6K antibody (1A5, CellSignaling) labeled with Europium-N-1-ITC (Eu) (10.4 Eu per antibody,PerkinElmer). The DELFIA Assay buffer and Enhancement solution can bepurchased from PerkinElmer. 45 μL of the terminated kinase reactionmixture is transferred to a MaxiSorp plate (Nunc) containing 55 μL PBS.The His6-S6K is allowed to attach for 2 hours after which the wells areaspirated and washed once with PBS. 100 μL of DELFIA Assay buffer with40 ng/mL Eu-P(T389)—S6K antibody is added. The antibody binding iscontinued for 1 hour with gentle agitation. The wells are then aspiratedand washed 4 times with PBS containing 0.05% Tween-20 (PBST). 100 μL ofDELFIA Enhancement solution is added to each well and the plates areread in a PerkinElmer Victor model plate reader. Data obtained is usedto calculate enzymatic activity and enzyme inhibition by potentialinhibitors.

PI3K-Alpha and PI3K-Gamma Fluorescence Polarization Assay Protocols

The reaction buffer was 20 mM HEPES, pH 7.5, 2 mM MgCl₂, 0.05% CHAPS;and 0.01% βME (added fresh). The Stop/Detection Buffer was 100 mM HEPES,pH 7.5, 4 mM EDTA, 0.05% CHAPS; ATP 20 mM in water; PIP2 (diC8, Echelon,Salt Lake City Utah cat #P-4508) 1 mM in water (MW=856.5). The GST-GRPwas 1.75 mg/mL or 1.4 mg/mL in 10% glycerol. The Red detector (TAMRA)was 2.5 μM. Nunc 384-well black polypropylene fluorescent plates wereused for PI3K assays.

The assay is run by placing 5 μL of diluted enzyme per well, then 5 μLof diluted compound (or 9.5 μL enzyme then 0.5 μL compound in DMSO) isadded and mixed. Then, 10 μL substrate is added to start the reaction.The samples are incubated 30-60 minutes, then the reaction is stopped byadding 20 μL stop/detector mix. PI3K is diluted with reaction buffer(e.g., 5 μL or 7.5 μL PI3K into 620 μL reaction buffer), and 5 μL ofdiluted enzyme is used per well. A 5 μL portion of reaction buffer or ofdrug diluted in buffer (e.g., 4 μL/100 so final DMSO is 1% in reaction)is added to each. Pipetting up and down mixes the samples.Alternatively, the enzyme can be diluted to 1215 μL. In this case 9.8 μLis added per well and 0.2 μL compound is added in DMSO.

To prepare 1 mL of substrate solution, 955 μL reaction buffer, 40 μLPIP2, and 2.5 μL ATP are mixed. 10 μL of substrate is added to each wellto start the reaction. This results in 20 μM PIP2, and 25 μM ATP perreaction. The stop/detector mix is prepared by mixing 4 μL Red detectorand 1.6 μL or 2.0 μL GST-GRP with 1 mL stop buffer, which results in 10nM probe and 70 nM GST-GRP. 20 μL of the stop/detector mix is added toeach well to stop the reaction. The plates are read after 30-90 minuteskeeping the red probe solutions dark. For the zero time point,stop/detector mix is added to the enzyme just before adding substrate.For an extra control, stop/detector mix is added to buffer (no enzyme)and substrate or to just buffer (no substrate). Pooled PI3K preparationshad a protein concentration of 0.25 mg/mL. The recommended reaction has0.06 μL per 20 μL (0.015 μg/20 μL) or 0.01125 μg/15 μL or 0.75 μg/mL.

Plates are read on machines with filters for TAMRA. The units are mPwith no enzyme controls reading app 190-220 mP units. Fully activeenzyme reduces fluorescence polarization down to 70-100 mP after 30minutes. An active compound raises the mP values halfway to control orto 120-150 mP units.

In Vitro Cell Culture Growth Assay Methods

Cell Lines used are human breast MDA-MB-361, human prostate PC3-mm2, andhuman prostate LNCap tumor cell lines. Cells are plated in 96-wellculture plates at approximately 3000 cells per well. One day followingplating, various concentrations of PI3K inhibitors in DMSO are added tocells (final DMSO concentration in cell assays is 0.25%). Three daysafter drug treatment, viable cell densities are determined by cellmediated metabolic conversion of the dye MTS, a well-establishedindicator of cell proliferation in vitro. Cell growth assays areperformed using kits purchased from Promega Corporation (Madison, Wis.),following the protocol provided by the vendor. Measuring absorbance at490 nm generates MTS assay results. Compound effect on cellproliferation is assessed relative to untreated control cell growth. Thedrug concentration that conferred 50% inhibition of growth is determinedas IC₅₀ (μM).

hSMG-1 Kinase Assay

The human SMG-1 (hSMG-1) kinase assay employs the recombinant hSMG-1protein prepared from transiently transfected HEK293 cells and a GST-p53(aa 1-70) fusion substrate protein derived from cellular tumorsuppressor gene p53. The routine assay is performed in a 96-well plateformat as follows. Enzymes were first diluted in kinase assay buffer (10mM HEPES, pH 7.4, 50 mM NaCl, 0.2 mM DTT, 50 mM β-glycerophosphate, 0.5μM microcystin LR, 10 mM MnCl₂). To each well, 12 μL of the dilutedenzyme were mixed briefly with 0.5 μL test inhibitor or control vehicledimethylsulfoxide (DMSO). The kinase reaction was initiated by adding12.5 μL kinase assay buffer containing ATP and GST-p53 to give a finalreaction volume of 25 μL containing 400-800 ng/mL FLAG-hSMG-1, 0.5 μgGST-p53, 10 μM ATP. The reaction was carried out at room temperature for1.0 hour before terminated by addition of 25 μl stop solution. The assaymixture was then transferred to FluoroNunc Plates with MaxiSorp Surface(Nunc #439-454). The plates were incubated at room temperature for 2 hr(4° C. for overnight) to achieve efficient binding of substrate proteinto the plate. The plates were aspirated, washed with PBS.Phospho-substrate proteins were detected by incubating for 1 hour with125 ng of europium-labeled anti-mouse secondary antibody (PerkinElmerAD2027) and the primary phospho(S15)-p53 monoclonal antibody (CellSignal #9286) in 1001 DELFIA assay buffer (PerkinElmer #1244-111).Plates were then washed and incubated for 0.5 hour with 100 μl of DELFIAenhancement solution (PerkinElmer #1244-105). DELFIA assay results arerecorded in a Victor Plate Reader (PerkinElmer). Data obtained were usedto calculate enzymatic activity and enzyme inhibition by potentialinhibitors.

Table 2 shows the results of the described PI3K-α, PI3K-γ, and mTORkinase assays.

TABLE 2 Example IC₅₀ PI3Kα nM IC₅₀ PI3Kγ nM IC₅₀ mTOR μM 1 3 29 0.0013 22 35 0.001 3 3 27 0.00385 4 2 23 0.0017 5 17 438 0.0063 6 6 53 0.0067 >10000 >100000 >4,0000 8 20 220 0.008 9 10 65 0.004 10 75 289 0.068 1161 528 0.00925 12 248 815 0.011 13 51 879 0.0115 14 25 154 0.00845 15 23177 0.0025 16 >10,000 >100000 0.01205 17 8 90 0.01395 18 9 71 0.036 1923 206 0.039 20 41 258 0.0305 21 22 92 0.00175 22 12 142 0.00475 23 1851 0.00205 24 22 99 0.0027 25 58 105 0.00405 26 680 10,000 0.0025 271230 >10,000 0.00415 28 54 5550 0.00095 29 2690 >10,000 0.0028 302120 >10,000 0.00265 31 142 3520 0.00049 32 45 2540 0.00029 33 NA NA0.091 34 9 95 0.00049 35 6 54 0.00021 36 17 150 0.00051 37 39 1550.00195 38 7 91 0.00028 39 14 75 0.00032 40 21 136 0.00066 41 69 1220.0013 42 86 290 0.00335 43 28 35 0.00165 44 NA NA 0.0135 45 NA NA0.0036 46 208 4920 0.024 47 13 52 0.0016 48 6 40 0.0018 49 3 21 0.01 501 21 0.002 51 1 15 0.0019 52 2 38 0.001 53 45 403 0.024 54 10 88 0.0047555 205 1580 0.05 56 122 444 0.015 57 8 74 0.0165 58 13 85 0.0025 59 3 300.00105 60 5 36 0.0018 61 9 32 0.00076 62 2 24 0.00068 63 5 36 0.0019564 1457 1190 1.5 65 15 83 0.00505 66 7 30 0.00165 67 6 48 0.00145 68 0.37 0.00057 69 0.4 8 0.00085 70 2 20 0.0007 71 0.4 8 0.00067 72 2 190.00085 73 0.3 7 0.00077 74 0.4 8 0.00063 75 0.6 10 0.00075 76 0.4 80.00067 77 0.3 4 0.00068 78 3 23 0.00085 79 773 193 0.0051 80 851 21200.00715 81 2 38 0.001 82 3 21 0.0089 83 1 15 0.0019 84 10 88 0.00475 8545 403 0.018 86 122 444 0.01 87 205 1580 0.05 88 8 74 0.0165 89 10 310.0016 90 8 42 0.00083 91 6 73 0.00071 92 11 92 0.00235 93 12 1330.00855 94 5 56 0.001 95 48 101 0.00275 96 NA NA 0.0012 97 NA NA 0.001198 1350 9000 2.1 99 1520 7500 0.46 100 5 38 0.0035 101 6 33 0.00044 1026 84 0.0061 103 3 73 0.0053 104 19 234 0.015 105 14 112 0.0305 106 3931840 0.00755 107 115 1490 0.019 108 586 4150 0.019 109 1460 2960 0.0735110 884 3510 0.029 111 116 1830 0.0023 112 488 777 0.012 113 NA NA0.0037 114 106 1180 0.00315 115 109 2000 0.0032 116 1740 2310 0.0027 117177 3000 0.083 118 379 297 0.195 119 1240 7530 0.14 120 262 1550 0.079121 1850 4000 0.0435 122 1160 9500 0.0745 123 760 6350 0.115 124 16509650 0.155 125 840 8750 0.016 126 510 5510 0.0195 127 1390 4730 0.0515128 1330 10,000 0.031 129 7217 10,000 2.35 130 14 132 0.008 131 25 3360.0145 132 14 234 0.026 133 39 8890 0.043 134 20 183 0.0245 135 15 1430.034 136 208 4920 0.024 137 9 117 0.00855 138 123.5 459 0.0435 139 2443 0.074 140 27 100 0.027 141 241 3380 0.026 142 3 50 0.0011 143 2 220.0012 144 NA NA NA 145 574 1000 0.009 146 >10000 >100000 0.003 147 19306830 0.006 148 300 620 0.008 149 889 1400 0.08 150 832 >10,000 0.005 1510.6 8117 0.007 152 2 5 0.002 153 868 10,000 0.015 154 275 3820 0.064 1552300 4940 0.016 156 746 10,000 0.053 157 1451 7090 0.17 158 300 12900.007 159 133 3920 0.002 160 358 9070 0.007 161 39 155 0.03 162 10 4950.023 163 2 9 0.0039 164 378 1380 4 165 9 101 0.028 166 4 33 0.06 1670.8 7 0.00068 168 1 3 0.0036 169 408 7960 0.0083 170 384 9500 0.004 171300 9500 0.0012 172 435 10,000 0.008 173 1210 10,000 0.084 174 861 7270.0021 175 549 453 0.0048 176 1120 3730 0.022 177 5840 4120 0.0016178 >10,000 >10,000 0.014 179 1 13 0.001 180 531 8000 0.0016 181 4266730 0.011 182 308 5000 0.003 183 526 11000 0.014 184 30 143 0.004 185 118 0.0029 186 28 221 0.006 187 3 24 0.0035 188 7540 2380 0.011 189 19203 0.028 190 780 1320 0.0063 191 435 4630 0.016 192 1120 453 0.043 193401 3133 0.0008 194 NA NA 0.027 195 115 498 0.021 196 6 55 0.013 197 236 0.024 198 2 33 0.002 199 44 144 0.001 200 14 128 0.0065 201 28 6060.0009 202 NA NA 0.0055 203 NA NA 0.001 204 NA NA 0.0035 205 NA NA 0.002206 NA NA 0.056 207 NA NA 0.00084 208 Na NA 0.0005 209 24 99 0.009 210 631 NA 211 80 108 0.006 212 902 8770 0.0064 213 5280 10,000 0.0095 2142670 10,000 0.0029 215 187 3160 0.0012 216 521 7030 0.003 217 253 32300.0032 218 279 2780 0.0026 219 561 8280 0.0059 220 275 2830 0.0035 221214 4280 0.0027 222 152 572 0.0005 223 2 200 NA 224 444 5870 0.0004 225109 388 0.047 226 75 294 0.062 227 23 81 0.0073 228 46 280 0.051 229 1970 0.00077 230 22 119 0.0012 231 4 63 0.0025 232 6 37 0.083 233 55 1210.0079 234 4534 9534 NA 235 3206 4110 NA 236 3 15 0.011 237 2 23 0.003238 1 10 0.0036 239 11 38 0.0032 240 1 6 0.0016 241 6 23 0.009 242 2 240.007 243 1 9 0.0077 244 1 9 0.0051 245 1 13 0.01 246 1 12 0.015 247 2 50.019 248 2 18 0.0064 249 25 216 0.002 250 21 190 0.0009 251 2 21 0.006252 22 184 0.018 253 8 267 0.009 254 63 253 0.017 255 48 85 0.016 256 68182 0.032 257 90 323 0.085 258 403 6170 0.0023 259 408 5410 0.0024 260417 4730 0.0009 261 158 2530 0.00031 262 105 954 0.00029 263 3 20 0.001264 947 5440 NA 265 1079 10,000 0.0015 266 16 93 0.0017 267 17 58 0.0035268 12 41 0.00039 269 6 140 0.08 270 68 318 0.16 271 2 23 0.013 272 5 540.03 273 4 33 0.0008 274 34 616 0.059 275 46 711 0.07 276 34 597 0.06277 30 276 0.06 278 26 344 0.25 279 10 70 0.035 280 5 29 0.004 281 21884981 2.8 282 10 32 0.0047 283 1 11 0.0031 284 0.7 12 0.0009 285 11273433 0.001 286 4195 10,000 120 287 253 3304 0.00016 288 226 2784 0.00097289 955 3880 0.0015 290 97 166 0.15 291 368 711 0.19 292 1501 3693 0.07293 764 533 0.5 294 9 26 0.018 295 19 81 0.029 296 13 35 0.021 297 38 700.01 298 2 24 0.021 299 3 34 0.08 300 39 106 0.0053 301 21 58 0.0008 30235 263 0.036 303 NA NA 0.017 304 2 18 0.0025 305 1 18 0.0006 306 1 190.0021 307 3 30 0.0028 308 3 14 0.0029 309 12 95 0.0035 310 14 82 0.0059311 40 125 0.012 312 3440 10,000 0.037 313 1730 7490 0.037 314 182010,000 0.08 315 1100 7900 0.005 316 1410 2690 0.071 317 216 6830 0.084318 15.5 679 0.855 319 80 1446 0.0044 320 3.3 25 0.0129 321 25 1160.0165 322 2.4 30 0.006 323 2.9 32 0.007 324 1 22 0.0052 325 74 62440.0046 326 830 6189 0.0122 327 394 5899 0.0063 328 261 14,000 0.0046 3299.5 385 0.00068 330 42 827 0.0033 331 NA NA 0.0035 332 NA NA 0.011 333NA NA 0.0058 334 16 680 0.0009 335 81 144 0.004 336 40 44 0.0036 337 798 0.07 338 3 77 0.022 339 71 485 0.09 340 92 706 0.046 341 10 48 0.012342 20 127 0.0066 343 97 6700 0.04 344 1610 4140 1.5 345 43 112 0.08 34643 89 0.023 347 796 8440 NA 348 1030 10,000 NA 349 59 163 NA 350 1 7 NA351 3 16 0.0042 352 13.5 732 0.00024 353 8.5 501 0.00022 354 69 62240.0046 355 830 6189 0.012 356 394 5899 0.0063 357 261 14000 0.0046 358 9363 0.00068 359 42 827 0.0034 360 6672 >10000 0.082 361 6028 >100000.0013 362 3090 >10000 0.00074 363 1097 7142 0.00077 364 1465 80380.0035 365 6340 >10000 0.0012 366 585 2996 0.0011 367 499 4076 0.001 368109 1936 0.00068 369 362 2560 0.0013 370 483 3502 0.00085 371 389 22560.00084 372 961 7245 0.00025 373 70 2962 0.00016 374 64 3915 0.00014 37544 2589 0.00015 376 2602 >10000 0.0023 377 2614 4718 0.0039 378 25065375 0.0054 379 4749 5255 0.0073 380 3344 3559 0.0051 381 2955 53950.0059 382 522 4306 0.0045 383 2978 3609 0.0061 384 4220 5381 0.0064 3853397 4692 0.0057 386 5122 4476 0.0042 387 3416 2858 0.0032 388 3450 42850.0048 389 4766 5663 0.0065 390 2467 2354 0.012 391 2398 4000 0.0096 3921178 2781 0.0055 393 444 1539 0.0036 394 592 3226 0.0088 395 584 22210.014 396 586 2432 0.01 397 173 2073 0.00016 398 644 3909 0.00021 399330 1691 0.0011 400 846 4099 0.0017 401 413 3247 0.002 402 543 36430.0018 403 314 2383 0.00075 404 63 433 0.00069 405 50 193 0.00064 406478 1881 0.00038 407 766 2255 0.00052 408 876 3342 0.00072 409 856 44870.0015 410 826 5684 0.0023 411 1896 >10000 0.0036 412 1230 7483 0.0073413 1518 >10000 0.0092 414 969 5453 0.0069 415 787 3263 0.00038 416 4462505 0.00055 417 656 4299 0.0011 418 520 3476 0.0015 419 610 4272 0.0017420 593 4363 0.00063 421 414 1571 0.00072 422 269 1221 0.00079 423 6101854 0.0011 424 576 1871 0.0014 425 309 2383 0.0012 426 1224 8477 0.053427 580 1419 0.0013 428 450 840 0.0014 429 483 1005 0.0019 430 402 4840.0017 431 43 340 0.001 432 90 480 0.00069 433 220 1510 0.0023 434 5714740 0.00056 435 643 4603 0.00075 436 749 3119 0.00062 437 381 16120.00056 438 77 663 0.00081 439 182 1283 0.00042 440 1006 >10000 0.0012441 970 >10000 0.0012 442 1756 >10000 0.0015 443 427 1883 0.00089 444 601099 0.00057 445 100 1002 0.00041 446 835 4013 0.00082 447 390 28020.0019 448 519 >10000 0.0023 449 287 1640 0.0019 450 76 888 0.0017 45185 702 0.0014 452 41 502 0.00055 453 659 4273 0.0033 454 278 1490 0.0002455 113 1390 0.0003 456 150 1547 0.0007 457 63 839 0.0002 458 33 5120.0002 459 26 483 0.0003 460 143 1083 0.0004 461 482 4415 0.0011 462<0.001 463 0.017 464 0.001 465 0.001 466 0.001 467 <0.001 468 <0.001 4690.023 470 0.007 471 0.000 472 0.035 473 0.035 474 0.048 475 18.500 4760.005 477 14.000 478 1.1 6.0 0.00089 479 <2.1 14.0 0.0017 480 13.0 53.00.0029 481 11.0 65.0 0.0023 482 0.6 10.0 0.00305 483 28.5 150.0 0.00155484 1.0 8.0 0.00063 485 1.4 10.0 0.00125 486 1.1 7.0 0.0045 487 32.327.0 0.0018 488 42.0 180.0 0.0034 489 3671.7 9045.0 0.0022 490 586.01077.0 0.0116 491 3.5 17.0 0.0011 492 6.5 35.0 0.018 493 2924.0 1078.00.0325 494 16.5 104.0 0.0042 495 <1.00 6.0 0.00195 496 NA NA NA 497 3.019.0 0.0046 498 <1.70 2.5 0.00235 499 <1.90 4.5 0.0022 500 0.4 10.00.00109 501 <1.75 6.5 0.00069 502 0.5 6.0 0.001 503 0.5 1.8 504 1.8 10.00.00135 505 0.6 5.0 NA 506 0.3 7.0 NA 507 1.6 8.7 0.0032 508 <1.9 12.50.00097 509 11.5 662.5 0.00045 510 1.1 6.3 0.00089 511 2.3 10.3 0.00052512 <1.9 10.0 0.00012 513 <2.4 12.0 0.00012 514 1.6 15.0 0.00017 515 0.47.6 0.00155 516 2.1 17.0 NA 517 3.4 18.5 0.00106 518 0.9 6.5 0.0011 519<1.1 4.8 0.00071 520 1.4 8.0 0.00038 521 1.4 6.0 0.0003 522 1.4 7.50.00106 523 3.2 9.5 0.00043 524 0.8 10.0 0.00026 525 NA NA NA 526 96.56701.5 0.0475 527 20.5 127.0 0.0093 528 1612.0 4140.0 1.6 529 10.5 48.50.0155 530 92.0 705.5 0.0495 531 71.5 484.5 0.08 532 3.0 76.5 0.019 5337.0 98.5 0.0705 534 2.1 11.1 0.0534 535 43.5 112.0 0.0815 536 1.5 13.00.0094 537 43.5 89.0 0.000022 538 333.0 197.0 0.000125 539 1.1 16.00.0000085 540 54.0 121.0 0.0000034 541 28.000 57.000 0.017 542 8.00067.000 0.0215 543 3.500 15.500 0.042 544 3.500 20.500 0.017 545 4.00017.000 0.0109 546 3.500 73.500 0.000225 547 11.000 70.000 0.00775 54840.000 387.000 0.00975 549 724.000 4541 0.0265 550 47.000 374.000 0.0124551 24.000 117.500 0.01 552 11.500 127.000 0.00355 553 12.500 72.0000.0195 554 15.000 156.500 0.0119 555 87.500 378.500 0.405 556 8.50054.000 0.0044 557 18.000 64.000 0.00855 558 17.000 41.000 0.0061 5592.000 13.500 0.01005 560 269.000 504.500 0.1 561 11.5 59.0 0.006 562 1.010.5 0.004 563 2.5 33.5 0.003 564 0.6 16.5 0.001 565 4.1 38.0 0.001 5662.6 18.0 0.002 567 14.5 90.0 0.002 568 3.5 18.0 0.010 569 74.5 375.00.008 570 5.5 48.0 0.013 571 21.0 108.0 0.000 572 0.9 15.0 0.000 573 6.564.0 0.004 574 1.0 12.5 0.006 575 3.0 19.0 0.015 576 761.0 2081.0 0.140577 63.0 104.0 0.030 578 2406.0 2511.0 2.100 579 462.0 658.0 0.120 580465.0 1315.0 0.100 581 113.5 461.0 0.037 582 513.0 1094.0 0.230 583123.0 718.0 0.048 584 585 65.0 131.0 0.012 586 947.0 1246.0 0.365 587350.0 675.0 0.100 588 524.5 2249.0 0.054 589 718.0 1615.0 0.057 590343.0 403.5 0.049 591 250.0 726.0 0.033 592 25.5 122.0 0.009 593 40.0143.0 0.012 594 349.5 744.0 0.022 595 6.5 58.5 0.010 596 5.0 40.5 0.013597 5.0 58.0 0.011 598 5.5 40.0 0.010 599 64.5 190.0 0.013 600 45.5161.5 0.008 601 3.5 57.5 0.003 602 7.0 46.5 0.011 603 8.5 50.5 0.017 6043.5 55.5 0.010 605 2.2 46.0 0.003 606 12.0 87.0 0.026 607 12.0 94.00.019 608 9.0 107.0 0.005 609 11.5 93.5 0.003 610 3.5 50.5 0.005 61118.5 151.5 0.013 612 5.5 67.0 0.061 613 3.8 53.5 0.001 614 2.7 32.50.001 615 26.5 115.5 0.001 616 4.0 58.5 0.001 617 2.5 27.0 0.001 618 2.018.5 0.001 619 33.0 137.0 0.001 620 4.0 32.5 0.003 621 3.5 43.5 0.001622 3.0 50.5 0.000 623 12.5 104.0 0.001 624 17.5 58.5 0.001 625 16.5102.5 0.003 626 59.0 207.5 0.001 627 18.5 101.5 0.002 628 629 26.0 95.00.004 630 13.5 84.5 0.001 631 28.0 133.0 0.004 632 15.0 74.5 0.001 63311.5 175.0 0.001 634 6.0 121.5 0.000 635 22.0 377.5 0.000 636 231.0468.5 0.027 637 21.5 190.5 0.004 638 16.0 113.5 0.002 639 14.5 123.00.001 640 345.0 795.0 2.800 641 88.5 275.5 0.007 642 69.0 254.5 0.001643 6.2 42.5 0.007 644 7.8 59.5 0.001 645 105.0 230.5 0.120 646 23.085.5 0.006 647 24.3 107.0 0.003 648 2.0 27.0 0.003 649 6.4 38.0 0.006650 23.5 103.5 0.022 651 71.0 247.5 0.014 652 36.0 84.5 0.004 653 4.134.0 0.007 654 6.0 70.0 0.008 655 91.5 745.5 0.625 656 73.0 651.0 0.019657 11.5 127.5 0.385 658 41.5 265.0 0.020 659 3621.0 10000.0 0.720 6607.5 168.5 0.305 661 56.5 461.5 0.580 662 34.3 197.0 0.770 663 47.3 296.00.590 664 NA NA NA 665 71.0 283.5 0.445 666 11.5 662.5 0.000 667 1021081 0.000405 668 122 625.000 0.00056 669 8.0 89.0 0.00048 670 5.0 53.00.000212 671 17.5 150.5 0.000505 672 39.5 154.5 0.00195 673 7.0 98.70.00043 674 14.0 74.5 0.000325 675 21.0 135.5 0.00066 676 69.5 122.00.0013 677 86.5 290.0 0.00335 678 21.3 45.3 0.001168 679 1575.0 9500.00.0135 680 504.0 2083.0 0.0036 681 2547 >10,000 0.091 682 84.3 1282.50.0885 683 121.3 1329.0 0.025 684 154.3 2345.0 0.0235 685 7.0 26.50.000825 686 77.0 540.0 0.026 687 4.0 39.5 0.00485 688 3.0 35.5 0.008689 217.4 2482 0.03902 690 5.0 83.5 0.000525 691 6.0 199.0 0.00135 6923.2 29.0 0.00375 693 69.0 289.0 0.00135 694 2.0 40.0 0.000245 695 4.070.5 0.00028 696 4.5 73.5 0.000275 697 2.7 42.7 0.000459 698 2.7 44.70.000302 699 5.0 62.5 0.0003 700 2.5 41.5 0.00053 701 2.0 25.0 0.00036702 6.5 125.5 0.000555 703 1.5 23.5 0.00051 704 7217 >10,000 2.35 70513.5 132.0 0.0124 706 25.5 336.0 0.0145 707 14.0 234.5 0.034 708 39.58890.5 0.043 709 20.0 182.5 0.0245 710 15.5 143.5 0.034 711 207.5 4919.50.02 712 9.5 117.0 0.00855 713 36.0 444.0 0.0009 714 15.5 69.0 0.00645715 59.5 146.5 0.006 716 NA NA NA 717 444.0 5874.0 0.000395 718 40.5210.5 0.055 719 17.5 96.0 0.00015 720 0.4 7.0 0.0077 721 0.6 10.50.00565 722 0.8 9.5 0.0145 723 1.3 13.5 0.0225 724 1.5 4.0 0.0185 7252.0 20.5 0.0082 726 25.0 216.5 0.0025 727 21.0 189.5 0.000805 728 10.547.0 0.00038 729 14.5 100.0 0.00185 730 15.5 64.5 0.0043 731 33.0 413.00.059 732 44.0 478.0 0.069 733 31.5 412.0 0.0755 734 25.5 210.0 0.0595735 26.5 289.5 0.1225 736 9.5 53.5 0.0036 737 7.0 30.0 0.00445 738 NA NANA 739 NA NA NA 740 11.5 34.5 0.00405 741 2188 4981 2.80 742 97.0 166.00.145 743 368.0 711.0 0.19 744 1501.0 3693.0 0.068 745 764.0 533.0 0.47746 23.5 99.0 0.001265 747 40.0 44.0 0.00345 748 NA NA NA 749 59.0 163.50.002 750 NA NA NA 751 143.0 403.5 0.003 752 1.2 18.5 0.00029 753 2.031.0 0.000315 754 3.0 28.0 0.000327 755 2.0 26.5 0.00057 756 0.5 7.00.0002 757 5.5 37.5 0.00028 758 2.0 16.0 0.00017 759 2.0 38.0 0.00016760 4.3 28.3 0.00021 761 2.0 19.0 0.00012 762 2.7 19.7 0.000428 763 3.024.0 0.000445 764 8.5 67.5 0.00021 765 8.5 78.5 0.000195 766 24.0 85.50.001315 767 2.1 17.0 0.0002 768 1.2 18.5 0.000115 769 2.1 17.5 0.00023770 30.5 99.0 0.00027 771 19.5 66.0 0.000215 772 0.8 9.5 0.00029 773 3.036.5 0.000305 774 2.0 41.5 0.00023 775 2.5 46.5 0.00023 776 3.0 29.50.000345 777 4.0 39.0 0.000265 778 11.5 126.0 0.00028 779 4.2 49.70.00023 780 NA NA NA 781 136.0 374.5 0.0305 782 124.5 251.5 0.11 783346.0 736.0 0.295 784 40.5 174.0 0.088 785 6.0 45.5 0.0555 786 30.5129.0 0.089 787 10.5 145.5 0.0585 788 13.0 160.0 0.026 789 870.0 1163.00.059 790 244.0 593.0 0.065 791 12.5 64.5 0.00068 792 3.3 35.5 0.00081793 1.0 15.0 0.00042 794 4.1 26.0 0.00063 795 2.7 26.5 0.000425 796 2.631.5 0.00039 797 11.5 76.0 0.0013 798 4.1 43.5 0.000445 799 5.0 71.50.0005 800 5.5 35.5 0.00072 801 5.0 38.0 0.000455 802 3.5 23.0 0.000675803 3.0 29.0 0.00019 804 6.0 59.5 0.000425 805 6.5 64.0 0.000415 806 4.547.0 0.00024 807 Na NA NA 808 381.0 1261.0 0.26 809 395.0 2189.0 0.067810 2.8 30.5 0.00205 811 3.2 33.5 0.0015 812 2.8 30.5 0.002 813 3.1 30.00.0019 814 0.8 10.0 0.00105 815 1.9 24.0 0.000765 816 2.4 26.0 0.001065817 NA NA NA 818 37.7 185.0 0.002 819 44.0 357.5 0.017 820 6.1 67.00.000515 821 9.3 58.3 0.0034 822 3.0 31.5 0.000335 823 661.0 2788.00.0000015 824 2 17 NA 825 2 13 NA 826 15 96 1.200 827 2.150 17.000 0.295828 2.050 13.000 0.185 829 10.500 188.500 0.520 830 4.150 70.500 0.305831 3.300 87.500 0.265 832 61.500 341.500 0.165 833 5.600 81.500 0.185834 4.800 86.500 0.680 835 5.850 66.000 0.780 836 5.100 41.000 0.665 8373.700 19.500 0.515 838 4.000 69.500 1.550

Table 3 shows the results of the described hSMG-1 kinase assay.

TABLE 3 hSMG-1 IC₅₀ Example (μM) 462 0.001 463 0.510 464 0.003 465 0.005466 0.000 467 0.000 468 <0.000 469 0.130 470 0.195 471 0.005 472 0.200473 3.650 474 5.650 475 >20 476 0.019 477 9.250

Table 4 shows the results of the described MDA-MB-361, PC3-mm2, andLNCap assays.

TABLE 4 IC₅₀ MDA-MB- 361 IC₅₀ PC3-mm2 IC₅₀ LNCap Example (nM) (nM) (nM)1 45.0 43.0 2 45.0 43.0 3 45.0 43.0 4 45.0 43.0 5 45.0 43.0 6 45.0 43.07 ND ND 8 407.0 293.0 9 102.0 161.0 10 2709.0 1782.0 11 794.0 5630.5 12ND ND 13 603.0 845.0 14 376.0 590.0 15 255.0 328.0 16 ND ND 17 501.0994.0 18 2656.0 7102.0 19 1031.0 1596.0 20 >10000 >10000 21 129.0 246.022 1424.0 2445.0 23 104.0 147.0 24 122.0 142.0 25 264.0 258.0 26 ND ND190.0 27 ND ND 350.0 28 ND ND 2.4 29 ND ND 180.0 30 ND ND 90.0 31 ND ND45.0 32 ND ND 0.7 33 ND ND 34 28.0 41.0 35 22.5 27.5 36 73.0 98.0 3798.0 176.0 38 15.0 28.0 39 22.0 30.0 40 <30 62.0 41 167.0 301.0 42 345.03600.0 43 35.8 40.0 44 ND ND 45 ND ND 46 ND ND 47 116.0 95.0 48 38.048.0 49 84.0 79.0 50 36.0 39.0 51 <30 <30 52 <30 49.0 53 662.0 987.0 54133.0 214.0 55 ND ND 56 ND ND 57 119.0 187.0 58 115.0 45.0 59 14.0 16.060 83.0 92.0 61 48.0 23.0 62 27.0 34.0 63 69.0 62.0 64 ND ND 65 151.0267.0 66 59.0 66.0 67 816.0 28.0 68 <3 11.0 69 10.0 13.0 70 19.0 24.0 71<9.8 18.3 72 1.0 13.0 73 30.0 107.0 74 <3 8.3 75 <3 7.0 76 4.0 13.1 77<30 <30 78 68.0 31.0 79 ND 320.0 80 ND 320.0 81 ND ND 82 ND ND 83 ND ND84 ND ND 85 ND ND 86 ND ND 87 ND ND 88 ND ND 89 30.0 47.0 90 19.0 19.091 25.0 1567.0 92 140.0 87.0 93 42.0 60.0 94 54.0 82.0 95 333.0 364.0 965.0 33.0 97 <30 52.0 98 ND ND 99 ND ND 100 56.0 56.0 101 32.7 37.3 3.0102 592.0 854.0 103 2917.0 4453.0 104 412.0 684.0 105 3710.0 >10000 106ND ND 370.0 107 ND ND 1000.0 108 ND ND 320.0 109 ND ND 1900.0 110 ND ND220.0 111 ND ND 58.0 112 ND ND 300.0 113 ND ND 120.0 114 ND ND 38.0 115ND ND 200.0 116 ND ND 70.0 117 ND ND 700.0 118 ND ND 3000.0 119 ND ND2800.0 120 ND ND 1200.0 121 ND ND 1000.0 122 ND ND 900.0 123 ND ND4100.0 124 ND ND 1950.0 125 ND ND 1000.0 126 ND ND 1300.0 127 ND ND1350.0 128 ND ND 30000.0 129 ND ND 130 191.0 416.0 131 696.0 839.0 132586.0 1012.0 133 795.0 1950.0 134 805.0 857.0 135 533.0 509.0 136 ND ND137 582.0 551.0 138 ND ND 680.0 139 ND ND 180.0 140 225 279 141 ND ND142 5 33 143 ND 52 144 ND ND 1500 145 ND ND 120 146 ND ND 5 147 ND ND1000 148 ND ND 680 149 ND ND 32000 150 ND ND 290 151 ND 14 152 9 14 153ND ND 4200 154 ND ND 22000 155 ND ND 400 156 ND ND 22000 157 ND ND 2700158 ND ND 49 159 ND ND 1.2 160 ND ND 220 161 328 675 162 ND ND 163 10.728.3 164 ND ND 165 210 333 166 134 249 167 ND 10 168 ND ND 169 ND ND5000 170 ND ND 4500 171 ND ND 5200 172 ND ND 9500 173 ND ND 2500 174 NDND 4.25 175 ND ND 9.5 176 ND ND 1000 177 ND ND 600 178 ND ND 850 179 ND8.333 180 ND ND 5800 181 ND ND 3400 182 ND ND 3500 183 ND ND 8500 1841246 2094 185 5 13 186 473 703 187 11 41 188 ND ND 189 84 99 190 ND ND950 191 ND ND 220 192 ND ND 620 193 ND ND 105 194 ND ND 600 195 ND ND196 50 82 197 17 49 198 ND 43 199 96 93 200 162 248 201 29 44 202 ND ND700 203 ND ND 78 204 ND ND 6000 205 ND ND 400 206 ND ND 5100 207 ND ND33.333 208 ND ND 50 209 174 278 210 ND ND 211 254 389 212 ND ND 420 213ND ND 420 214 ND ND 700 215 ND ND 30 216 0 ND 50 217 ND ND 13 218 ND ND12 219 ND ND 40 220 ND ND 40 221 ND ND 120 222 ND ND 10 223 187 229 224ND ND 225 ND ND 226 ND ND 227 1495 4026 228 3924 7174 229 35.75 40 230ND ND 231 20 121 232 38 177 233 1214 3337 234 ND ND 10000 235 ND ND 7900236 22.333 67 237 28 69 238 23 61 239 184 317 240 ND 12 241 24 135 24211 49 243 15 34 244 ND 71 245 110 374 246 35 91 247 30 111 248 ND 69 24992 142 250 14 31 251 ND 65 252 219 747 253 12 574 254 ND ND 255 174 328256 ND ND 257 ND ND 258 ND ND 60 259 ND ND 580 260 ND ND 380 261 ND ND30 262 ND ND 22 263 68 31 264 ND ND 265 ND ND 1.7 266 ND ND 267 94 200268 59 107 38 269 ND 144 270 397 953 271 68 129 272 70 340 273 32 80 2741000 1491 275 3100 4309 276 1347 1654 277 530 572 278 2297 3701 279 176247 280 176 404 281 ND ND 282 83 84 283 12.333 33.333 284 12 36.333 285ND ND 4 286 ND ND 32000 287 ND ND 288 ND ND 3 289 ND ND 3 290 ND ND 291ND ND 292 ND ND 293 ND ND 294 69 154 295 133 189 296 83 133 297 115 290298 38 165 299 73 219 300 297 340 301 430 759 302 299 539 303 ND ND 0.8304 7 39.333 305 4 46 306 7 30 307 ND 362 308 4 53 309 64 109 310 44 117311 126 366 312 ND ND 80 313 ND ND 100 314 ND ND 550 315 ND ND 300 316ND ND 320 317 ND ND 120 318 ND ND 1000 319 ND ND 220 320 32.333 73.667321 106 325 322 13 86 323 ND 77 324 4 35 325 ND ND 310 326 ND ND 580 327ND ND 400 328 ND ND 1500 329 ND ND 5900 330 ND ND 260 331 0 0 0 332 0 00 333 0 0 0 334 0 0 0 335 0 0 0 336 56 45 0 337 142 373 338 122 266 339ND ND 340 ND ND 341 150 237 342 1256 2429 343 ND ND 344 ND ND 345 554395 346 ND ND 347 ND ND 9 348 ND ND 349 87 81 350 ND 8.5 351 50 66 352ND ND <0.8 353 ND ND <0.8 354 ND ND 310 355 ND ND 580 356 ND ND 400 357ND ND 1500 358 ND ND 5900 359 ND ND 260 360 ND ND 10000 361 ND ND 2.2362 ND ND 1 363 ND ND 1.2 364 ND ND 70 365 ND ND 3 366 ND ND 2.8 367 NDND 5 368 ND ND 0.7 369 ND ND 3 370 ND ND 0.8 371 ND ND 0.8 372 ND ND 0.8373 ND ND 1 374 ND ND <0.8 375 ND ND <0.8 376 ND ND 50 377 ND ND 90 378ND ND 50 379 ND ND 140 380 ND ND 300 381 ND ND 140 382 ND ND 48 383 NDND 150 384 ND ND 50 385 ND ND 70 386 ND ND 140 387 ND ND 70 388 ND ND110 389 ND ND 240 390 ND ND 650 391 ND ND 300 392 ND ND 480 393 ND ND580 394 ND ND 800 395 ND ND 590 396 ND ND 280 397 ND ND 7 398 ND ND 12399 ND ND 3 400 ND ND 12 401 ND ND 21 402 ND ND 7 403 ND ND 8 404 ND ND60 405 ND ND 25 406 ND ND 2.4 407 ND ND 0.8 408 ND ND 9 409 ND ND 50 410ND ND 110 411 ND ND 250 412 ND ND 25 413 ND ND 150 414 ND ND 120 415 NDND 29 416 ND ND 12 417 ND ND 6 418 ND ND 40 419 ND ND 12 420 ND ND 2 421ND ND 1 422 ND ND 2 423 ND ND 2.8 424 ND ND 1 425 ND ND 2.8 426 ND ND700 427 ND ND 7 428 ND ND 1 429 ND ND 9 430 ND ND 16 431 ND ND <0.8 432ND ND <0.8 433 ND ND 40 434 ND ND <0.8 435 ND ND 4 436 ND ND 10 437 NDND 1 438 ND ND <0.8 439 ND ND 1 440 ND ND 1 441 ND ND 6 442 ND ND 13 443ND ND 8 444 ND ND <0.8 445 ND ND <0.8 446 ND ND 15 447 ND ND 8 448 ND ND18 449 ND ND 40 450 ND ND <0.8 451 ND ND <0.8 452 ND ND <0.8 453 ND ND30 454 ND ND <0.8 455 ND ND <0.8 456 ND ND <0.8 457 ND ND <0.8 458 ND ND8 459 ND ND <0.8 460 ND ND <0.8 461 ND ND 68 462 ND ND ND 463 ND ND ND464 ND ND ND 465 ND ND ND 466 ND ND 420 467 ND ND 170 468 ND ND 50 469ND ND 2800 470 ND ND 1000 471 ND ND 130 472 ND ND 3800 473 ND ND ND 474ND ND ND 475 ND ND ND 476 ND ND ND 477 ND ND ND 478 <3.080 8.5 479 6 21480 ND ND 481 ND ND 482 ND ND 483 ND ND 484 ND ND 485 ND ND 486 7.0 39.3487 175.0 339.0 488 ND ND 489 ND ND 4300 490 ND ND 491 8.0 35.0 492 26.057.0 493 ND ND 494 115.0 276.0 495 4.0 13.1 496 ND ND 497 50.0 66.0 4984.0 16.5 499 21.0 31.0 500 1.0 6.5 501 <31 41 502 4.0 11.0 503 7.5 12.5504 22.5 25.5 505 12.3 33.3 506 <21.7 12 507 10.7 28.3 508 12.0 36.3 509ND ND <0.8 510 ND ND 511 2.0 10.0 512 1.0 8.0 513 2.0 13.0 514 <3.2 12515 3 12 516 ND ND 517 18.0 7.0 518 4.0 24.0 519 3.0 9.0 520 5.0 18.0521 8.0 27.0 522 3.0 11.0 523 ND ND 524 ND ND 525 ND ND 526 ND ND 5271256.0 2429.0 528 ND ND 529 150.0 237.0 530 ND ND 531 ND ND 532 122.0266.0 533 142.0 373.0 534 32.3 73.7 535 554.0 395.0 536 22.3 67.0 537<31 <31 538 ND ND 539 9.0 161.0 540 165.0 309.0 541 964.0 1764.0 542281.0 569.0 543 <31 262.0 544 58.0 253.0 545 30.0 219.0 546 7.0 25.0 54768.0 197.0 548 524.0 869.0 549 ND ND 550 315.0 711.0 551 106.0 270.0 552105.0 243.0 553 113.0 522.0 554 521.0 >1000 555 ND ND 556 128.0 379.0557 34.0 31.0 558 751.0 939.0 559 8.0 149.0 560 ND ND 561 66.0 218.0 5623.0 93.0 563 10.0 171.0 564 1.0 7.0 565 9.0 27.0 566 28.0 55.0 567 106.0130.0 568 18.0 107.0 569 ND ND 570 28.0 344.0 571 90.0 168.0 572 13.056.0 573 99.0 206.0 574 6.0 25.0 575 15.0 242.0 576 ND ND 577 ND ND 578ND ND 579 ND ND 580 ND ND 581 ND ND 582 ND ND 583 ND ND 584 ND ND 585 NDND 586 ND ND 587 ND ND 588 ND ND 589 ND ND 590 ND ND 591 ND ND 592 239.0718.0 593 >1000 >1000 594 ND ND 595 43.0 193.0 596 26.0 155.0 597 45.0229.0 598 22.0 214.0 599 ND ND 600 ND ND 601 22.0 155.0 602 17.0 122.0603 17.0 137.0 604 4.0 73.0 605 7.0 92.0 606 28.0 173.0 607 24.0 213.0608 52.0 298.0 609 24.0 26.0 610 28.0 297.0 611 194.0 581.0 612 38.0227.0 613 6.0 21.0 614 4.0 15.0 615 88.0 123.0 616 4.0 21.0 617 4.0 17.0618 2.0 13.0 619 ND ND 620 4.0 16.0 621 8.0 35.0 622 5.0 25.0 623 6.032.0 624 4.0 19.0 625 12.0 43.0 626 ND ND 627 16.0 55.0 628 ND ND 62928.0 133.0 630 5.0 23.0 631 28.0 120.0 632 9.0 38.0 633 15.0 64.0 6345.0 16.0 635 26.0 106.0 636 ND ND 637 26.0 62.0 638 9.0 44.0 639 16.027.0 640 ND ND 641 ND ND 642 ND ND 643 19.0 59.0 644 51.0 185.0 645 NDND 646 32.0 223.0 647 46.0 136.0 648 12.0 34.0 649 9.0 37.0 650 ND ND651 ND ND 652 ND ND 653 ND ND 654 ND ND 655 ND ND 656 ND ND 657 ND ND658 ND ND 659 ND ND 660 ND ND 661 ND ND 662 ND ND 663 ND ND 664 ND ND665 ND ND 666 ND ND 667 ND ND 60.0 668 ND ND 0.8 669 28.0 41.0 670 22.527.5 671 73.0 98.0 672 98.0 176.0 673 15.0 28.0 674 22.0 30.0 675 <3062.0 676 167.0 301.0 677 345.0 3600.0 678 35.8 40.0 679 ND ND 680 ND ND681 ND ND 682 1044.0 766.0 683 673.0 584.0 684 806.0 1015.0685 >10000 >10000 686 569.0 1105.0 687 355.0 389.0 688 1412.0 1950.0 68953.0 85.0 690 112.0 405.0 691 52.0 131.0 692 97.0 326.0 693 ND ND 694 <311.0 695 6.0 7.0 696 13.0 13.0 697 <30 <30 698 <3 6.0 699 36.0 40.0 7005.0 20.0 701 <30 <30 702 4.0 14.0 703 <3 13.0 704 ND ND 705 191.0 416.0706 696.0 839.0 707 586.0 1012.0 708 795.0 1950.0 709 805.0 857.0 710533.0 509.0 711 ND ND 712 582.0 551.0 713 29.0 44.0 714 162.0 248.0 715254.0 389.0 716 ND ND 717 ND ND <0.8 718 3924.0 7174.0 719 <31 <31 72015.0 34.0 721 <31 71.0 722 110.0 374.0 723 35.0 91.0 724 30.0 111.0 725<31 69.0 726 92.0 142.0 727 14.0 31.0 728 59.0 107.0 38.000 729 <31 <31730 94.0 200.0 731 1000.0 1491.0 732 3100.0 4309.0 733 1347.0 1654.0 734530.0 572.0 735 2297.0 3701.0 736 176.0 247.0 737 176.0 404.0 738 ND ND739 ND ND 740 83.0 84.0 741 ND ND 742 ND ND 743 ND ND 744 ND ND 745 NDND 746 93.0 118.0 747 56.0 45.0 748 ND ND 749 87.0 81.0 750 ND ND 751144.0 238.0 752 <3 6.0 753 4.0 14.0 754 31.3 70.8 755 3.0 13.0 756 <312.000 757 <3 6.000 758 3.0 14.0 759 1.0 10.0 760 0.0 4.0 761 <3 4.0 7628.0 7.0 763 4.0 7.0 764 628.0 678.0 765 21.0 27.0 766 26.0 50.0 767 5.013.0 768 7.0 8.0 769 6.0 14.0 770 40.0 25.0 771 >1000 >1000 772 5.0 15.0773 4.0 6.0 774 14.0 19.0 775 5.0 7.0 776 <3.2 6.0 777 2.0 4.0 778 17.029.0 779 13.0 23.0 780 ND ND 781 ND ND 782 ND ND 783 ND ND784 >1000 >1000 785 >1000 >1000 786 >1000 >1000 787 >1000 >1000788 >1000 >1000 789 ND ND 790 ND ND 791 11.0 42.0 792 2.0 16.0 793 2.026.0 794 2.0 20.0 795 <3.2 10.0 796 2.0 18.0 797 11.0 29.0 798 3.0 24.0799 <3.2 24.0 800 1.0 11.0 801 3.0 32.0 802 3.0 50.0 803 1.0 6.0 804 3.011.0 805 3.0 13.0 806 <3.2 9.0 807 35.000 37.000 808 ND ND 809 ND ND 8102.0 26.0 811 2.0 19.0 812 3.0 23.0 813 <3.2 24.0 814 4.0 37.0 815 3.024.0 816 2.0 11.0 817 ND ND 818 129.0 237.0 819 442.0 768.0 820 ND ND821 ND ND 822 ND ND 823 ND ND 55.0 823 ND ND 825 ND ND 826 >1000 >1000

While particular aspects of the present invention have been illustratedand described, it would be obvious to those skilled in the art thatvarious other changes and modifications can be made without departingfrom the spirit and scope of the invention. It is therefore intended tocover in the appended claims all such changes and modifications that arewithin the scope of this invention.

Throughout this application, various publications are referenced. Thedisclosures of these publications in their entireties are herebyincorporated by reference into this application in order to more fullydescribe the state of the art as known to those skilled therein as ofthe date of the invention described and claimed herein.

1. A compound of the Formula I:

wherein: R¹ is

wherein: R⁶, R⁷, R⁸, R⁹ are each independently selected from the groupconsisting of a hydrogen atom, and a C₁-C₆alkyl optionally substitutedwith C₂-C₆alkenyl, C₄-C₆alkadienyl, C₂-C₆alkynyl or C₄-C₆alkadiynyl; andone of R⁶ and R⁹, R⁶ and R⁸, or R⁷ and R⁸ are attached by a (CH₂)_(y),(CH₂—X—), or (CH₂—X—CH₂) linking group wherein one or two hydrogen atomsin the linking group may be independently replaced by C₁-C₆alkyl,(C₁-C₆alkyl)NH—, (C₁-C₆alkyl)₂N—, (C₆-C₁₄aryl)alkyl-O—, halo, 3-10membered C₁-C₉heterocyclyl optionally substituted with C₁-C₆alkyl-, HO—,or H₂N—; wherein any two hydrogen atoms on the same carbon atom of thelinking group can be replaced by an oxygen atom to form an oxo (═O)substituent, y is 1, 2 or 3; X is O, S(O)_(n), or NR¹⁰; n is 0, 1 or 2;the dashed line ----- represents an optional second bond; R¹⁰ isselected from the group consisting of H, C₁-C₆alkyl, —SO₂(C₁-C₆alkyl),—COO(C₁-C₆alkyl), —CONH(C₁-C₆alkyl), —CON(C₁-C₆alkyl)₂, —CO(C₁-C₆alkyl),and —SO₂NHR¹¹; R¹¹ is selected from the group consisting of H,C₁-C₆alkyl optionally substituted with OH, NR¹¹R¹¹ or a 3-7 memberedC₁-C₆heterocyclyl, —CO(C₁-C₆alkyl), optionally substituted C₆-C₁₀aryl,and optionally substituted C₁-C₉heteroaryl; R² is optionally substitutedC₆-C₁₄aryl-NH—COR³, optionally substituted C₁-C₉heteroaryl-NH—COR³,—CH═CH—C₆-C₁₀aryl-NH—COR³ or —CH═CH—C₁-C₉heteroaryl-NH—COR³; R³ is OR⁵,NR⁵R⁵ or NHR⁵; R⁵ is independently selected from the group consisting ofC₁-C₆alkyl, C₃-C₆alkenyl, C₃-C₆alkynyl, optionally substitutedC₆-C₁₀aryl, C₁-C₆haloalkyl, optionally substituted C₁-C₉heteroaryl,C₁-C₆hydroxylalkyl-, C₃-C₁₀saturated or unsaturated mono or bicyclicC₃-C₁₀cycloalkyl optionally substituted with OH, NR¹¹R¹¹ or 3-7 memberedC₁-C₆heterocyclyl, and 3-10 membered saturated or unsaturated mono orbicyclic C₁-C₉heterocyclyl, with the proviso that three-memberedcycloalkyl and heterocyclyl rings are saturated; or two R⁵ groups takentogether with the nitrogen atom to which they are attached form a 3 to 8membered ring system optionally substituted with C₁-C₆alkyl, which ringsystem is saturated or unsaturated and has, in addition to said nitrogenatom, 0 to 2 heteroatom ring members selected from O, S, S(O), S(O)₂ andNR¹⁰; R⁴ is selected from the group consisting of: a) C₁-C₆alkyloptionally substituted with: i) 3-10 membered C₁-C₉heterocyclyloptionally substituted with C₁-C₆alkyl-, ii) H₂N—, iii) (C₁-C₆alkyl)NH—,iv) (C₁-C₆alkyl)₂N—, v) NH(CH₂)_(a)N(C₁-C₆alkyl)₂ wherein a is 2, 3 or4, and vi) CHO, b) C₃-C₆alkenyl, c) C₃-C₆alkynyl, d) —O—C₁-C₈alkyloptionally substituted with —O—C₁-C₈alkyl, e) —O—C₃-C₈alkenyl, f)—O—C₃-C₈alkynyl, g) saturated or unsaturated mono or bicyclicC₃-C₈cycloalkyl, and h) saturated or unsaturated mono or bicyclic—O—C₃-C₁₂cycloalkyl, all the above optionally substituted with OH,NR¹¹R¹¹ or a 3-7 membered C₁-C₆heterocyclyl optionally substituted withC₁-C₆alkyl-, provided that an OH or NR¹¹R¹¹ is not directly bonded to acarbon atom that is double- or triple-bonded to another carbon atom; i)—CH═CH—C₆-C₁₀aryl; j) —CH═CH—C₁-C₉heteroaryl; k) optionally substitutedC₆-C₁₀aryl; l) optionally substituted 5-10 membered C₁-C₉heteroarylattached to the triazine moiety via a carbon atom; m) 3-10 memberedsaturated or unsaturated mono or bicyclic C₁-C₉heterocyclyl attached tothe triazine moiety through a carbon or nitrogen atom and optionallysubstituted with from 1 to 3 substituents independently selected from:OH, NR¹¹R¹¹, C₁-C₆alkyl, (C₁-C₆alkyl)amido-, (C₁-C₆alkyl)C(O)—,(C₁-C₆alkoxy)carbonyl-, adamantyl, C₁-C₆hydroxylalkyl-, or a 3-7membered C₁-C₆heterocyclyl, with the proviso that 3 memberedheterocyclyl is saturated and attached to the triazine moiety through anitrogen atom, and 5 membered bicyclic heterocyclyl is saturated; n)optionally substituted —O—C₆-C₁₀aryl; o) optionally substituted—O—C₁-C₉heteroaryl; p) —O-(3-12 membered saturated or unsaturated monoor bicyclic)C₁-C₉heterocyclyl optionally substituted with(C₁-C₆alkoxy)carbonyl-, H₂NS(O)₂—, or C₁-C₆alkyl further optionallysubstituted with OH, NR¹¹R¹¹ or a 3-7 membered C₁-C₆heterocyclyl, withthe proviso that three membered heterocyclyl is saturated; q)—NHC₆-C₁₀aryl, r) —NHC₁-C₉heteroaryl, s) —NHNH₂, t) —NHNHC₁-C₆alkyl, u)—NHN(C₁-C₆alkyl)₂, v) —NHOH, w) —COOH, x) —COO—C₁-C₆alkyl, y)—CONR¹²R¹³, z) —NR¹²R¹³,

wherein Z is CH₂, O, S(O), or NR¹⁰; ee) halogen, ff)C₆-C₁₄aryl-S(O)₂—NH—, gg) R¹¹NHC(O)NH—O—, and hh) optionally substituted5-membered monocyclic C₁-C₄heteroaryl attached to the triazine moietyvia a nitrogen atom; R¹² and R¹³ are each independently selected from H,optionally mono or disubstituted C₁-C₈alkyl, optionally substitutedC₃-C₈alkenyl, and optionally substituted C₃-C₈alkynyl, the optionalsubstituents being selected from C₁-C₆alkoxy, OH, NR¹¹R¹¹, and 3-7membered C₁-C₆heterocyclyl, provided that an OH or NR¹¹R¹¹ is notdirectly bonded to a carbon atom that is double- or triple-bonded toanother carbon atom; or R¹² and R¹³ taken together with the nitrogenatom to which they are attached form a 3 to 8 membered ring systemoptionally substituted with C₁-C₆alkyl, which ring system is saturatedor unsaturated and has, in addition to said nitrogen atom, 0 to 2heteroatom ring members selected from O, S(O)_(n) and NR¹⁰; or R¹² andR¹³ taken together with the nitrogen atom to which they are attachedform

wherein a and b are each independently —CH₂—, O, S, or NR¹⁰, and x is1-3; C₁-C₉heteroaryl refers to a 5-10 membered aromatic ring systemhaving one or more rings and 1, 2, 3 or 4 ring members independentlyselected from O, NR¹⁰, and S(O),; C₁-C₉heterocyclyl refers to a 3-10membered ring system having one or more rings and 1, 2, 3 or 4 ringmembers independently selected from O, NR¹⁰, and S(O)_(n); andoptionally substituted aryl and heteroaryl groups are unsubstituted orare substituted with 1 or 2 moieties selected from the group consistingof: a) C₁-C₆alkyl optionally substituted with OH, NH₂, NH(C₁-C₆alkyl),N(C₁-C₆alkyl)₂, —NH(CH₂)_(w)N(C₁-C₆alkyl)₂ wherein w is 2, 3 or 4, or3-10 membered C₁-C₉heterocyclyl optionally substituted with from 1 to 3independently selected C₁-C₆alkyl- substituents; b) halogen; c) hydroxy;d) NH₂; e) NO₂; f) SO₂NH₂; g) COOH; h) COO(C₁-C₆alkyl); i)NHCOO(C₁-C₆alkyl); j) NH(C₁-C₆alkyl); k) N(C₁-C₆alkyl)₂; l)C(O)NR^(a)R^(b), wherein R^(a) is H or C₁-C₆alkyl, and R^(b) is H,C₁-C₆alkyl, (C₆-C₁₄aryl)alkyl-, or (C₁-C₉heteroaryl)alkyl-; m) -Y-Q,wherein Y is: i) O, ii) NH, iii) N(C₁-C₆alkyl), iv) NHSO₂, v) SO₂NH, vi)NHCONH, vii) NHCON(C₁-C₆alkyl), viii) S(O)_(q), q is 0, 1 or 2,ix)-C(O)NH—, x) —C(O)N(CH₃)—, xi) —NHC(O)— xii) C(O), or xiii) absent,and Q is selected from: i) C₆-C₁₀aryl, optionally substituted with from1 to 3 substituents independently selected from: A) C₁-C₆alkoxy-optionally substituted with 1) H₂N—, 2) (C₁-C₆alkyl)amino-, 3)di(C₁-C₆alkyl)amino-, 4) C₁-C₉heterocyclyl- optionally substituted byC₁-C₆alkyl-, or 5) hydroxyl, B) (C₁-C₆alkoxy)carbonyl-, C)(C₁-C₆alkoxy)C(O)NH—, D) C₁-C₆alkyl- optionally substituted with 1)H₂N—, 2) (C₁-C₆alkyl)amino-, or 3) di(C₁-C₆alkyl)amino-, E)(C₁-C₆alkyl)amino-, F) di(C₁-C₆alkyl)amino-, G) (C₁-C₆alkyl)amido-optionally substituted with 1) H₂N—, 2) (C₁-C₆alkyl)amino-, or 3)di(C₁-C₆alkyl)amino-, H) (C₁-C₆alkyl)carboxyamido-, I)C₁-C₉heterocyclyl-optionally substituted by C₁-C₆alkyl- orC₁-C₆hydroxylalkyl-, J) heterocyclyl(C₁-C₆alkyl)- optionally substitutedby C₁-C₆alkyl-, K) halogen, L) hydroxyl, M) C₁-C₆hydroxylalkyl-, N)perfluoro(C₁-C₆)alkyl-, O) H₂N—, P)O₂N—, Q) H₂NSO₂—, R) HO₂C—, andS)NC—, ii) 5-10 membered C₁-C₉heteroaryl, optionally substituted withfrom 1 to 3 substituents independently selected from: A)C₁-C₆alkoxy-optionally substituted with 1) H₂N—, 2) (C₁-C₆alkyl)amino-,3) di(C₁-C₆alkyl)amino-, 4) C₁-C₉heterocyclyl- optionally substituted byC₁-C₆alkyl-, or 5) hydroxyl, B) (C₁-C₆alkoxy)carbonyl-, C)(C₁-C₆alkoxy)C(O)NH—, D) C₁-C₆alkyl- optionally substituted with 1)H₂N—, 2) (C₁-C₆alkyl)amino-, or 3) di(C₁-C₆alkyl)amino-, E)(C₁-C₆alkyl)amino-, F) di(C₁-C₆alkyl)amino-, G)(C₁-C₆alkyl)amido-optionally substituted with 1) H₂N—, 2)(C₁-C₆alkyl)amino-, or 3) di(C₁-C₆alkyl)amino-, H)(C₁-C₆alkyl)carboxyamido-, I) C₁-C₉heterocyclyl- optionally substitutedby C₁-C₆alkyl- or C₁-C₆hydroxylalkyl-, J) heterocyclyl(C₁-C₆alkyl)-optionally substituted by C₁-C₆alkyl-, K) halogen, L) hydroxyl, M)C₁-C₆hydroxylalkyl-, N) perfluoro(C₁-C₆)alkyl-, O) H₂N—, P)O₂N—, Q)H₂NSO₂—, R) HO₂C—, and S)NC—, iii) 3-10 membered C₁-C₉heterocyclyl,optionally substituted with from 1 to 3 substituents independentlyselected from: A) C₁-C₆alkyl-, B) heterocyclyl(C₁-C₆alkyl)-, C)(C₆-C₁₄aryl)alkyl-, D) C₁-C₈acyl-, E) (C₁-C₆alkoxy)carbonyl-, F)(C₁-C₆alkyl)carboxyl-, G) halogen, H) C₁-C₆haloalkyl-, I) hydroxyl, J)C₁-C₆hydroxyalkyl-, K) H₂N—, L) (C₁-C₆alkyl)amino-, M)di(C₁-C₆alkyl)amino-, N) HO₂C—, O) (C₁-C₆alkoxy)carbonyl-, P)(C₁-C₆alkyl)carboxyl-, Q) (C₁-C₆alkyl)amido-, R) H₂NC(O)—, S)(C₁-C₆alkyl)carboxyamido-, T) 5-10 membered C₁-C₉heteroaryl, U)C₆-C₁₄ary, V) C₃-C₈cycloalkyl W) 3-10 membered C₁-C₉heterocyclyl, and X)—NO₂; iv) C₃-C₁₀cycloalkyl, v) C₁-C₆alkyl, vi) C₂-C₆alkenyl, vii)C₂-C₆alkynyl, viii) C₁-C₆hydroxyalkyl-, ix) (CH₂)_(v)O(C₁-C₆alkyl), x)(CH₂)_(v)NH₂, xi) (CH₂)_(v)NH(C₁-C₆alkyl), xii) (CH₂)_(v)N(C₁-C₆alkyl)₂,xiii) O(CH₂)_(v)N(C₁-C₆alkyl)₂, xiv) (CH₂)_(v)C₆-C₁₀aryl, xv)-CN, xvi)(CH₂)_(v) 5-10 membered C₁-C₉heteroaryl, xvii) (CH₂)_(v) 3-10 memberedC₁-C₉heterocyclyl, optionally substituted by C₁-C₆alkyl-, wherein v is1, 2, 3 or 4, and xviii) C₁-C₆ perfluoroalkyl-; and n) C(O)R^(c) whereinR^(c) is: i) H, ii) C₁-C₆alkyl, or iii) C₃-C₆cycloalkyl, andpharmaceutically acceptable salts thereof.
 2. The compound of claim 1wherein R¹ is

and pharmaceutically acceptable salts thereof.
 3. The compound of claim2 wherein R¹ is

and pharmaceutically acceptable salts thereof.
 4. The compound of claim3 wherein R² is optionally substituted C₆-C₁₄aryl-NH—COR³.
 5. Thecompound of claim 4 wherein R² is optionally substituted phenyl-NH—COR³.6. The compound of claim 5 wherein R³ is NHR⁵.
 7. The compound of claim6 wherein R⁵ is C₁-C₉heteroaryl.
 8. The compound of claim 7 wherein R⁵is pyridyl.
 9. The compound of claim 8 wherein R⁵ is 4-pyridyl.
 10. Thecompound of any one of claims 1-9 wherein R⁴ is

and pharmaceutically acceptable salts thereof.
 11. The compound of claim10 wherein R⁴ is


12. The compound selected from the group consisting of:1-{4-[4-morpholin-4-yl-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-phenylurea;1-(4-fluorophenyl)-3-{4-[4-morpholin-4-yl-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}urea;1-(4-methylphenyl)-3-{4-[4-morpholin-4-yl-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}urea;1-[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-yl-1,3,5-triazin-2-yl)phenyl]-3-methylurea;2-hydroxyethyl[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-yl-1,3,5-triazin-2-yl)phenyl]carbamate;1-[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(4-methylpiperazin-1-yl)phenyl]urea;1-[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-yl-1,3,5-triazin-2-yl)phenyl]-3-ethylurea;1-cyclopropyl-3-[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-yl-1,3,5-triazin-2-yl)phenyl]urea;1-[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-yl-1,3,5-triazin-2-yl)phenyl]-3-pyridin-4-ylurea;1-[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(hydroxymethyl)phenyl]urea;1-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;4-[({4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide;1-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea;1-(4-fluorophenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;1-[4-(hydroxymethyl)phenyl]-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;1-[4-(2-hydroxyethyl)phenyl]-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;2-(diethylamino)ethyl4-[({4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzoate;1-(4-methylphenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;1-(4-cyanophenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;1-[4-(4-methylpiperazin-1-yl)phenyl]-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;1-isopropyl-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;1-(2-hydroxyethyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;1-{4-[4-morpholin-4-yl-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea;1-{4-[4-morpholin-4-yl-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;t-butyl2-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-chloro-1,3,5-triazin-2-ylamino)ethylcarbamate;1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(piperidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea;1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea;1-{4-[4-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy)-6-morpholin-4-yl-[1,3,5]triazin-2-yl]-phenyl}-3-pyridin-4-yl-urea;4-(3-{4-[4-(8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy)-6-morpholin-4-yl-[1,3,5]triazin-2-yl]-phenyl}-ureido)-benzamide;tert-butyl4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-pyridin-4-ylureido)phenyl)-1,3,5-triazin-2-yl)piperazine-1-carboxylate;1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea;1-{4-[4-(4-methylpiperazin-1-yl)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;1-{4-[4-(4-benzylpiperazin-1-yl)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;1-(4-{4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-[4-(pyridin-3-ylmethyl)piperazin-1-yl]-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea;1-{4-[4-(4-acetylpiperazin-1-yl)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;1-(4-{4-[4-(N,N-dimethylglycyl)piperazin-1-yl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea;1-{4-[4-(4-isonicotinoylpiperazin-1-yl)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;methyl4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-{4-[(pyridin-4-ylcarbamoyl)-amino]phenyl}-1,3,5-triazin-2-yl]piperazine-1-carboxylate;1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-oxopiperidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea;1-{4-[4-(4-hydroxypiperidin-1-yl)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;1-(4-{4-[4-(benzylamino)piperidin-1-yl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea;1-(4-{4-[4-(methylamino)piperidin-1-yl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea;1-(4-{4-[4-(ethylamino)piperidin-1-yl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea;1-{4-[4-(4-{[2-(dimethylamino)ethyl]amino}piperidin-1-yl)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;1-{4-[4-(4-morpholin-4-ylpiperidin-1-yl)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea;1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(2-hydroxyethylamino)piperidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea;1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(2-morpholinoethylamino)piperidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea;methyl2-(1-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-pyridin-4-ylureido)phenyl)-1,3,5-triazin-2-yl)piperidin-4-ylamino)acetate;2-(1-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-pyridin-4-ylureido)phenyl)-1,3,5-triazin-2-yl)piperidin-4-ylamino)acetamidetert-butyl2-(1-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-pyridin-4-ylureido)phenyl)-1,3,5-triazin-2-yl)piperidin-4-ylamino)acetate;2-(1-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-pyridin-4-ylureido)phenyl)-1,3,5-triazin-2-yl)piperidin-4-ylamino)aceticacid;1-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-(2-piperidin-1-ylethoxy)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;methyl(4-{4-[4-({[4-(4-methylpiperazin-1-yl)phenyl]carbamoyl}amino)phenyl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)carbamate;1-cyclopropyl-3-(4-{4-[4-({[4-(4-methylpiperazin-1-yl)phenyl]carbamoyl}amino)phenyl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)urea;N′,N′″-{[6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazine-2,4-diyl]di-4,1-phenylene}bis{1-[4-(4-methylpiperazin-1-yl)phenyl]urea};1-[4-(4-methylpiperazin-1-yl)phenyl]-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-{4-[(pyridin-4-ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl]phenyl}urea;1-(4-{4-[(2-aminoethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-3-ylurea;1-{4-[4-anilino-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea;1-(4-{4-[(2-hydroxyethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-3-ylurea;1-{4-[4-(azetidin-3-ylamino)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea;1-(4-{4-[(2-morpholin-4-ylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-3-ylurea;1-(4-{4-[(3-aminopropyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-3-ylurea;1-(4-{4-[(4-cyclopentylpiperazin-1-yl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-3-ylurea;1-{4-[4-isopropoxy-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;1-{4-[4-isopropoxy-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-[4-(4-methylpiperazin-1-yl)phenyl]urea;1-{4-[4-chloro-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;1-(4-{4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-[(piperidin-4-ylmethyl)amino]-1,3,5-triazin-2-yl}phenyl)-3-pyridin-3-ylurea;1-(4-{4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-[(2-piperidin-4-ylethyl)amino]-1,3,5-triazin-2-yl}phenyl)-3-pyridin-3-ylurea;1-{4-[4-(3-methylimidazolidin-1-yl)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea;1-{4-[4-(3-methyltetrahydropyrimidin-1(2H)-yl)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea;1-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-(2-piperidin-1-ylethoxy)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea;1-(4-{4-[2-methoxy-1-(methoxymethyl)ethoxy]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea;1-(4-{4-[2-methoxy-1-(methoxymethyl)ethoxy]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-[4-(4-methylpiperazin-1-yl)phenyl]urea;2-hydroxyethyl(4-{4-[2-methoxy-1-(methoxymethyl)ethoxy]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)carbamate;1-(4-{4-[2-methoxy-1-(methoxymethyl)ethoxy]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-methylurea;1-cyclopropyl-3-(4-{4-[2-methoxy-1-(methoxymethyl)ethoxy]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)urea;1-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-(piperidin-3-ylmethoxy)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea;1-{4-[4-(4-aminobutoxy)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea;1-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-(2-piperidin-4-ylethoxy)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea;1-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-(piperidin-4-ylmethoxy)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea;1-(4-{4-morpholin-4-yl-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea;1-{4-[4-(methylamino)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea;1-{4-[4-(ethylamino)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea;1-{4-[4-(dimethylamino)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea;1-{4-[4-(isopropylamino)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea;1-{4-[4-(diethylamino)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea;1-(diethylcarbamoyl)-4-[({4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]pyridinium;1-(4-{4-[ethyl(methyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-3-ylurea;1-{4-[4-(sec-butylamino)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea;1-{4-[4-{[2-hydroxy-1-(hydroxymethyl)ethyl]amino}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea;1-(4-{4-[bis(2-hydroxyethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-3-ylurea;1-(4-{4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-3-ylurea;1-{4-[4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea;1-(4-{4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-[(4-piperazin-1-ylphenyl)amino]-1,3,5-triazin-2-yl}phenyl)-3-pyridin-3-ylurea;1-(4-{4-morpholin-4-yl-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-1,3,5-triazin-2-yl}phenyl)-3-{4-[(4-pyrrolidin-1-ylpiperidin-1-yl)carbonyl]phenyl}urea;1-methyl-3-(4-{4-[(1-methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)urea;1-cyclopropyl-3-(4-{4-[(1-methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)urea;1-(2-hydroxyethyl)-3-(4-{4-[(1-methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)urea;1-(4-{4-[(1-methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea;1-(4-{4-[(1-methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]urea;1-(4-{4-[(1-methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-[4-(4-methylpiperazin-1-yl)phenyl]urea;1-{4-[(2,2-dimethylhydrazino)carbonyl]phenyl}-3-(4-{4-[(1-methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)urea;4-{[(4-{4-[(1-methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)carbamoyl]amino}-N-pyrrolidin-1-ylbenzamide;1-{4-[2-(dimethylamino)ethoxy]phenyl}-3-(4-{4-[(1-methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)urea;1-[4-(hydroxymethyl)phenyl]-3-(4-{4-[(1-methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)urea;1-[4-(2-hydroxyethyl)phenyl]-3-(4-{4-[(1-methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)urea;1-[4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-yl-1,3,5-triazin-2-yl)phenyl]-3-pyridin-4-ylurea;1-[4-(4-methylpiperazin-1-yl)phenyl]-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;1-(4-acetylphenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;1-methyl-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)-1,3,5-triazin-2-yl]phenyl}urea;1-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea;1-(4-ethenylphenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;1-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;tert-butyl(1R,4R)-5-(4-morpholin-4-yl-6-{4-[(pyridin-4-ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate;tert-butyl(1R,4R)-5-[4-(4-{[(4-acetylphenyl)carbamoyl]amino}phenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate;1-(4-{4-[(2-methoxyethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-3-ylurea;1-{4-[4-{[(1S)-2-hydroxy-1-methylethyl]amino}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea;1-{4-[4-{[(1R)-2-hydroxy-1-methylethyl]amino}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea;1-(4-{4-[(2-hydroxy-1,1-dimethylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-3-ylurea;1-{4-[4-(tert-butylamino)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea;1-[4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-yl-1,3,5-triazin-2-yl)phenyl]-3-(4-piperazin-1-ylphenyl)urea;1-[4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(4-methylpiperazin-1-yl)phenyl]urea;1-{4-[2-(dimethylamino)ethoxy]phenyl}-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;1-{4-[4-(6-hydroxy-3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;tert-butyl-7-(4-morpholin-4-yl-6-{4-[(pyridin-4-ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate;1-{4-[4-(6,8-dioxa-3-azabicyclo[3.2.1]oct-3-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;1-[4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-yl-1,3,5-triazin-2-yl)phenyl]-3-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}urea;N-[4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-yl-1,3,5-triazin-2-yl)phenyl]piperazine-1-carboxamide;1-[4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(hydroxymethyl)phenyl]urea;1-[4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-yl-1,3,5-triazin-2-yl)phenyl]-3-{4-[(methylamino)methyl]phenyl}urea;1-{4-[2-(dimethylamino)ethoxy]phenyl}-3-[4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-yl-1,3,5-triazin-2-yl)phenyl]urea;1-{4-[4-morpholin-4-yl-6-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;1-{4-[4-(7-methyl-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;1-{4-[4-(7-acetyl-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;1-(4-{4-[7-(methylsulfonyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea;tert-butyl-(1R,4R)-5-{4-[4-({[4-(1-hydroxyethyl)phenyl]carbamoyl}amino)phenyl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate;1-[4-(4-methylpiperazin-1-yl)phenyl]-3-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}urea;1-{4-[4,6-di-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-1,3,5-triazin-2-yl]phenyl}-3-[4-(4-methylpiperazin-1-yl)phenyl]urea;1-{4-[4,6-di-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-1,3,5-triazin-2-yl]phenyl}-3-(4-piperazin-1-ylphenyl)urea;1-{4-[4,6-di-(1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-1,3,5-triazin-2-yl]phenyl}-3-[4-(4-methylpiperazin-1-yl)phenyl]urea;1-(2-fluoroethyl)-3-{4-[4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}urea;1-cyclopropyl-3-{4-[4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}urea;1-methyl-3-{4-[4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}urea;4-[({4-[4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide;1-{4-[4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-phenylurea;1-methyl-3-(4-{4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-[(4-piperazin-1-ylphenyl)amino]-1,3,5-triazin-2-yl}phenyl)urea;1-cyclopropyl-3-(4-{4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-[(4-piperazin-1-ylphenyl)amino]-1,3,5-triazin-2-yl}phenyl)urea;1-(2-fluoroethyl)-3-(4-{4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-[(4-piperazin-1-ylphenyl)amino]-1,3,5-triazin-2-yl}phenyl)urea;1-(2-hydroxyethyl)-3-(4-{4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-[(4-piperazin-1-ylphenyl)amino]-1,3,5-triazin-2-yl}phenyl)urea;4-{[(4-{4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-[(4-piperazin-1-ylphenyl)amino]-1,3,5-triazin-2-yl}phenyl)carbamoyl]amino}benzamide;1-(4-{4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-[(4-piperazin-1-ylphenyl)amino]-1,3,5-triazin-2-yl}phenyl)-3-phenylurea;1-methyl-3-{4-[4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}urea;1-cyclopropyl-3-{4-[4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}urea;1-(2-fluoroethyl)-3-{4-[4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}urea;4-[({4-[4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-yl]phenyl}carbamoyl)amino]benzamide;1-{4-[4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-phenylurea;1-(2,3′-bipyridin-4-yl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;1-(4-{4-[(2R,5S)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea;1-(4-{4-[(2R,5S)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl}phenyl)-3-[4-(4-methylpiperazin-1-yl)phenyl]urea;1-(6-chloropyridin-3-yl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;N-[4-({[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)phenyl]-N2,N2-dimethylglycinnamide;N-[4-({[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)phenyl]-2-pyrrolidin-1-ylacetamide;1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(piperazin-1-yl)phenylamino)-1,3,5-triazin-2-yl)phenyl)-3-methylurea;1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(piperazin-1-yl)phenylamino)-1,3,5-triazin-2-yl)phenyl)-3-cyclopropylurea;1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(piperazin-1-yl)phenylamino)-1,3,5-triazin-2-yl)phenyl)-3-(2-fluoroethyl)urea;1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(piperazin-1-yl)phenylamino)-1,3,5-triazin-2-yl)phenyl)-3-(2-hydroxyethyl)urea;4-(3-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(piperazin-1-yl)phenylamino)-1,3,5-triazin-2-yl)phenyl)ureido)benzamide;1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(piperazin-1-yl)phenylamino)-1,3,5-triazin-2-yl)phenyl)-3-phenylurea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(piperidin-4-ylamino)-1,3,5-triazin-2-yl)phenyl)-3-ethylurea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(piperidin-4-ylamino)-1,3,5-triazin-2-yl)phenyl)-3-ethylurea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(piperidin-4-ylamino)-1,3,5-triazin-2-yl)phenyl)-3-ethylurea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(piperidin-4-ylamino)-1,3,5-triazin-2-yl)phenyl)-3-ethylurea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(piperidin-4-ylamino)-1,3,5-triazin-2-yl)phenyl)-3-ethylurea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(piperidin-4-ylamino)-1,3,5-triazin-2-yl)phenyl)-3-ethylurea;1-(4-(4,6-di(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(piperazin-1-ylmethyl)phenyl)urea;1-(4-(4,6-di(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-((dimethylamino)methyl)phenyl)urea;1-(4-(aminomethyl)phenyl)-3-(4-(4,6-di(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)urea;1-(4-(4,6-di(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(pyrrolidin-1-ylmethyl)phenyl)urea;1-(4-(4,6-di(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)urea;1-(4-(4,6-di(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)urea;1-(4-(4,6-di(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-hydroxyethoxy)phenyl)urea;N-(4-(3-(4-(4,6-di(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)ureido)phenyl)-2-(dimethylamino)acetamide;N-(4-(3-(4-(4,6-di(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)ureido)phenyl)-2-(4-methylpiperazin-1-yl)acetamide;N-(4-(3-(4-(4,6-di(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)ureido)phenyl)-2-(pyrrolidin-1-yl)acetamide;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-3-yl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-triazin-2-yl)phenyl)-3-(4-((4-methylpiperazin-1-yl)methyl)phenyl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(piperazin-1-ylmethyl)phenyl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-triazin-2-yl)phenyl)-3-(4-((dimethylamino)methyl)phenyl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(aminomethyl)phenyl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(pyrrolidin-1-ylmethyl)phenyl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-(dimethylamino)ethoxy)phenyl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-triazin-2-yl)phenyl)-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(piperazin-1-yl)phenyl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(dimethylamino)piperidin-1-yl)phenyl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropyl(methyl)amino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropyl(methyl)amino)-1,3,5-triazin-2-yl)phenyl)-3-(4-((dimethylamino)methyl)phenyl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropyl(methyl)amino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-(dimethylamino)ethoxy)phenyl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-thiomorpholino-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-3-yl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-thiomorpholino-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-thiomorpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-thiomorpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-((dimethylamino)methyl)phenyl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-thiomorpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-(dimethylamino)ethoxy)phenyl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(3,6-dihydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(3,6-dihydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-(dimethylamino)ethoxy)phenyl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-((dimethylamino)methyl)phenyl)urea;1-(4-(4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea;1-(4-(4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-3-yl)urea;1-(4-(4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea;1-(4-(4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-((4-methylpiperazin-1-yl)methyl)phenyl)urea;1-(4-(4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(pyrrolidin-1-ylmethyl)phenyl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-3-yl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(pyrrolidin-1-ylmethyl)phenyl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-(dimethylamino)ethoxy)phenyl)urea;1-[4-(4-methylpiperazin-1-yl)phenyl]-3-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-(1-oxidothiomorpholin-4-yl)-1,3,5-triazin-2-yl]phenyl}urea1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-ethylpiperazin-1-yl)phenyl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazin-1-yl)phenyl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-cyclopropylpiperazin-1-yl)phenyl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(dimethylamino)piperidin-1-yl)phenyl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazine-1-carbonyl)phenyl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazine-1-carbonyl)phenyl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-ethylpiperazin-1-yl)phenyl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazin-1-yl)phenyl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-cyclopropylpiperazin-1-yl)phenyl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(dimethylamino)piperidin-1-yl)phenyl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazine-1-carbonyl)phenyl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazine-1-carbonyl)phenyl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)urea;4-(3-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)ureido)benzamide;4-(3-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)ureido)-N,N-dimethylbenzamide;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(pyrrolidine-1-carbonyl)phenyl)urea;4-(3-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)ureido)-N-(2-(dimethylamino)ethyl)benzamide;4-(3-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)ureido)-N-(2-(methylamino)ethyl)benzamide;4-(3-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)ureido)-N-(2-(dimethylamino)ethyl)-N-methylbenzamide;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(morpholine-4-carbonyl)phenyl)urea;1-(4-(2-aminoethylamino)phenyl)-3-(4-(4,6-di(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)urea;4-[({4-[4-{4-[(methylcarbamoyl)amino]phenyl}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide;3-[({4-[4-{4-[(methylcarbamoyl)amino]phenyl}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide;1-methyl-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-{4-[(pyridin-4-ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl]phenyl}urea;1-{4-[4-(5-hydroxy-3-oxa-7-azabicyclo[4.1.1]oct-7-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;1-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridazin-4-ylurea;N-[4-({[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)phenyl]-2-(4-methylpiperazin-1-yl)acetamide;1-(4-{[(3S)-3-(dimethylamino)pyrrolidin-1-yl]carbonyl}phenyl)-3-{4-[4-morpholin-;4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;1-(4-{[(3S)-3-(dimethylamino)pyrrolidin-1-yl]carbonyl}phenyl)-3-{4-[4-morpholin-;4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;N-[4-({[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)phenyl]-2-(4-methylpiperazin-1-yl)acetamide;1-(4-{4-[(2R,5S)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea;1-(4-{4-[(2R,5S)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-[4-(4-methylpiperazin-1-yl)phenyl]urea;1-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;4-[({4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide;1-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea;1-(4-fluorophenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;1-[4-(hydroxymethyl)phenyl]-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;1-[4-(2-hydroxyethyl)phenyl]-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;2-(diethylamino)ethyl4-[({4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzoate;1-(4-methylphenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;1-(4-cyanophenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;1-[4-(4-methylpiperazin-1-yl)phenyl]-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;1-isopropyl-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;1-(2-hydroxyethyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;1-{4-[4-(3-hydroxy-8-azabicyclo[3.2.1]oct-8-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-phenylurea;methyl4-[({4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzoate;N-[2-(dimethylamino)ethyl]-4-[({4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide;N,N-dimethyl-4-[({4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide;N-methyl-4-[({4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide;1-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;N-[2-(dimethylamino)ethyl]-N-methyl-4-[({4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide;N-(2-hydroxyethyl)-4-[({4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide;N-[3-(dimethylamino)propyl]-4-[({4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide;N-methyl-N-[2-(methylamino)ethyl]-4-[({4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide;N-(2-morpholin-4-ylethyl)-4-[({4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide;1-{4-[(3,5-dimethylpiperazin-1-yl)carbonyl]phenyl}-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;1-(diethylcarbamoyl)-4-[({4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]pyridinium;1-[4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-yl-1,3,5-triazin-2-yl)phenyl]-3-pyridin-4-ylurea;1-(4-acetylphenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;1-(4-ethenylphenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;1-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;1-{4-[2-(dimethylamino)ethoxy]phenyl}-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;1-{4-[4-(6,8-dioxa-3-azabicyclo[3.2.1]oct-3-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;tert-butyl7-(4-morpholin-4-yl-6-{4-[(pyridin-4-ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate;1-{4-[4-morpholin-4-yl-6-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;1-{4-[4-(7-methyl-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;1-{4-[4-(7-acetyl-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;1-(4-{4-[7-(methylsulfonyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea;1-(2-chloropyridin-4-yl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;1-(2,3′-bipyridin-4-yl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;1-(6-chloropyridin-3-yl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;1,3-bis{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;N-[2-(4-methylpiperazin-1-yl)ethyl]-4-[({4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide;1-{4-[(4-isopropylpiperazin-1-yl)carbonyl]phenyl}-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;1-{4-[(4-cyclopentylpiperazin-1-yl)carbonyl]phenyl}-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;1-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}-3-[4-(piperazin-1-ylcarbonyl)phenyl]urea;1-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}-3-{4-[(4-morpholin-4-ylpiperidin-1-yl)carbonyl]phenyl}urea;4-[({4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]-N-(2-pyrrolidin-1-ylethyl)benzamide;4-[({4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]-N-(2-piperidin-1-ylethyl)benzamide;1-[4-(1,4′-bipiperidin-1′-ylcarbonyl)phenyl]-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;1-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}-3-{4-[(4-pyrrolidin-1-ylpiperidin-1-yl)carbonyl]phenyl}urea;1-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}-3-[4-(thiomorpholin-4-ylcarbonyl)phenyl]urea;1-[4-(morpholin-4-ylcarbonyl)phenyl]-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;4-[({4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzoicacid;1-{4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;1-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-{4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}urea;N-[2-(dimethylamino)ethyl]-4-[({4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]-N-methylbenzamide;1-{4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}urea;methyl4-[({4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzoate;4-[({4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzoicacid;1-{4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-[4-(piperazin-1-ylcarbonyl)phenyl]urea;1-{4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-{4-[(4-isopropylpiperazin-1-yl)carbonyl]phenyl}urea;4-[({4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]-N-(2-pyrrolidin-1-ylethyl)benzamide;4-[({4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]-N-(2-piperidin-1-ylethyl)benzamide;1-{4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-{4-[(4-pyrrolidin-1-ylpiperidin-1-yl)carbonyl]phenyl}urea;1-[4-(1,4′-bipiperidin-1′-ylcarbonyl)phenyl]-3-{4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}urea;4-[({4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]-N-(2-pyridin-2-ylethyl)benzamide;4-[({4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]-N-(2-pyridin-4-ylethyl)benzamide;1-{4-[4-morpholin-4-yl-6-(3-oxa-9-azabicyclo[3.3.1]non-9-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;1-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-3-{4-[4-morpholin-4-yl-6-(3-oxa-9-azabicyclo[3.3.1]non-9-yl)-1,3,5-triazin-2-yl]phenyl}urea;1-{4-[4-morpholin-4-yl-6-(3-oxa-9-azabicyclo[3.3.1]non-9-yl)-1,3,5-triazin-2-yl]phenyl}-3-[4-(piperazin-1-ylcarbonyl)phenyl]urea;1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-9-azabicyclo[3.3.1]non-9-yl)-1,3,5-triazin-2-yl]phenyl}urea;N-[2-(dimethylamino)ethyl]-N-methyl-4-[({4-[4-morpholin-4-yl-6-(3-oxa-9-azabicyclo[3.3.1]non-9-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide;N-[2-(dimethylamino)ethyl]-4-[({4-[4-morpholin-4-yl-6-(3-oxa-9-azabicyclo[35.3.]non-9-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide;N-(2-methoxyethyl)-4-[({4-[4-morpholin-4-yl-6-(3-oxa-9-azabicyclo[3.3.1]non-9-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide;4-[({4-[4-morpholin-4-yl-6-(3-oxa-9-azabicyclo[3.3.1]non-9-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]-N-(2-pyrrolidin-1-ylethyl)benzamide;4-[({4-[4-morpholin-4-yl-6-(3-oxa-9-azabicyclo[3.3.1]non-9-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]-N-(2-piperidin-1-ylethyl)benzamide;1-{4-[4-morpholin-4-yl-6-(3-oxa-9-azabicyclo[3.3.1]non-9-yl)-1,3,5-triazin-2-yl]phenyl}-3-{4-[(4-pyrrolidin-1-ylpiperidin-1-yl)carbonyl]phenyl}urea;N-[2-(1-methylpyrrolidin-2-yl)ethyl]-4-[({4-[4-morpholin-4-yl-6-(3-oxa-9-azabicyclo[3.3.1]non-9-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide;N-methyl-N-[2-(methylamino)ethyl]-4-[({4-[4-morpholin-4-yl-6-(3-oxa-9-azabicyclo[3.3.1]non-9-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide;1-{4-[(4-ethylpiperazin-1-yl)carbonyl]phenyl}-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;1-{4-[(4-ethylpiperazin-1-yl)carbonyl]phenyl}-3-{4-[4-morpholin-4-yl-6-(3-oxa-9-azabicyclo[3.3.1]non-9-yl)-1,3,5-triazin-2-yl]phenyl}urea;1-(4-{[4-(1-methylethyl)piperazin-1-yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-9-azabicyclo[3.3.1]non-9-yl)-1,3,5-triazin-2-yl]phenyl}urea;1-{4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-{4-[(4-ethylpiperazin-1-yl)carbonyl]phenyl}urea;1-{4-[4-morpholin-4-yl-6-(2-oxa-5-azabicyclo[2.2.2]oct-5-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea;1-(1,3-dimethyl-1H-pyrazol-5-yl)-3-{4-[4-morpholin-4-yl-6-(2-oxa-5-azabicyclo[2.2.2]oct-5-yl)-1,3,5-triazin-2-yl]phenyl}urea;1-{4-[4-morpholin-4-yl-6-(2-oxa-5-azabicyclo[2.2.2]oct-5-yl)-1,3,5-triazin-2-yl]phenyl}-3-(1H-pyrazol-3-yl)urea;1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6-(2-oxa-5-azabicyclo[2.2.2]oct-5-yl)-1,3,5-triazin-2-yl]phenyl}urea;1-(4-{[4-(1-methylethyl)piperazin-1-yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6-(2-oxa-5-azabicyclo[2.2.2]oct-5-yl)-1,3,5-triazin-2-yl]phenyl}urea;1-{4-[(4-ethylpiperazin-1-yl)carbonyl]phenyl}-3-{4-[4-morpholin-4-yl-6-(2-oxa-5-azabicyclo[2.2.2]oct-5-yl)-1,3,5-triazin-2-yl]phenyl}urea;1-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-3-{4-[4-morpholin-4-yl-6-(2-oxa-5-azabicyclo[2.2.2]oct-5-yl)-1,3,5-triazin-2-yl]phenyl}urea;1-{4-[4-morpholin-4-yl-6-(2-oxa-5-azabicyclo[2.2.2]oct-5-yl)-1,3,5-triazin-2-yl]phenyl}-3-[4-(piperazin-1-ylcarbonyl)phenyl]urea;N-[2-(dimethylamino)ethyl]-4-[({4-[4-morpholin-4-yl-6-(2-oxa-5-azabicyclo[2.2.2]oct-5-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide;N-[2-(dimethylamino)ethyl]-N-methyl-4-[({4-[4-morpholin-4-yl-6-(2-oxa-5-azabicyclo[2.2.2]oct-5-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide;1-(4-{4-[(6S)-6-hydroxy-3-oxa-8-azabicyclo[3.2.1]oct-8-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea;1-(4-{4-[6-(benzyloxy)-3-oxa-8-azabicyclo[3.2.1]oct-8-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea;1-(4-{4-[(6R)-6-hydroxy-3-oxa-8-azabicyclo[3.2.1]oct-8-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea;1-(4-{4-[(6R)-6-(benzyloxy)-3-oxa-8-azabicyclo[3.2.1]oct-8-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea;1-{4-[(1,1-dioxidothiomorpholin-4-yl)carbonyl]phenyl}-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;1-[4-(4,6-di-3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(4-methylpiperazin-1-yl)phenyl]urea;1-(4-{[(3S)-3-(dimethylamino)pyrrolidin-1-yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;1-(4-{[(3R)-3-(dimethylamino)pyrrolidin-1-yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazin-1-yl)phenyl)urea;1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-ethylpiperazin-1-yl)phenyl)urea;1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(cyclopropylmethyl)piperazin-1-yl)phenyl)urea;1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-cyclopropylpiperazin-1-yl)phenyl)urea;1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(quinuclidin-4-yl)phenyl)urea;1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(dimethylamino)piperidin-1-yl)phenyl)urea;1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)urea;1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazine-1-carbonyl)phenyl)urea;1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazine-1-carbonyl)phenyl)urea;1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(dimethylamino)piperidine-1-carbonyl)phenyl)urea;1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-ethylpiperazine-1-carbonyl)phenyl)urea;1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-cyclopropylpiperazine-1-carbonyl)phenyl)urea;1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(cyclopropylmethyl)piperazine-1-carbonyl)phenyl)urea;1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)urea;1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(dimethylamino)piperidin-1-yl)phenyl)urea;1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(quinuclidin-4-yl)phenyl)urea;1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-cyclopropylpiperazin-1-yl)phenyl)urea;1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(cyclopropylmethyl)piperazin-1-yl)phenyl)urea;1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-ethylpiperazin-1-yl)phenyl)urea;1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazin-1-yl)phenyl)urea;1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea;1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazine-1-carbonyl)phenyl)urea;1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazine-1-carbonyl)phenyl)urea;1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(dimethylamino)piperidine-1-carbonyl)phenyl)urea;1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-ethylpiperazine-1-carbonyl)phenyl)urea;1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-cyclopropylpiperazine-1-carbonyl)phenyl)urea;1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(cyclopropylmethyl)piperazine-1-carbonyl)phenyl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazin-1-yl)phenyl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-ethylpiperazin-1-yl)phenyl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(cyclopropylmethyl)piperazin-1-yl)phenyl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-cyclopropylpiperazin-1-yl)phenyl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(quinuclidin-4-yl)phenyl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(dimethylamino)piperidin-1-yl)phenyl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazine-1-carbonyl)phenyl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazine-1-carbonyl)phenyl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(dimethylamino)piperidine-1-carbonyl)phenyl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-ethylpiperazine-1-carbonyl)phenyl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-cyclopropylpiperazine-1-carbonyl)phenyl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(cyclopropylmethyl)piperazine-1-carbonyl)phenyl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(dimethylamino)piperidin-1-yl)phenyl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(quinuclidin-4-yl)phenyl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-cyclopropylpiperazin-1-yl)phenyl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(cyclopropylmethyl)piperazin-1-yl)phenyl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-ethylpiperazin-1-yl)phenyl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazin-1-yl)phenyl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazine-1-carbonyl)phenyl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazine-1-carbonyl)phenyl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(dimethylamino)piperidine-1-carbonyl)phenyl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-ethylpiperazine-1-carbonyl)phenyl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-cyclopropylpiperazine-1-carbonyl)phenyl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(cyclopropylmethyl)piperazine-1-carbonyl)phenyl)urea;1-(4-(4,6-bis((1S,5S,6S)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea;1-(4-(4,6-bis((1S,5S,6S)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazin-1-yl)phenyl)urea;1-(4-(4,6-bis((1S,5S,6S)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-ethylpiperazin-1-yl)phenyl)urea;1-(4-(4,6-bis((1S,5S,6S)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(dimethylamino)piperidin-1-yl)phenyl)urea;1-(4-(4,6-bis((1S,5S,6S)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(quinuclidin-4-yl)phenyl)urea;1-(4-(4,6-bis((1S,5S,6S)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-cyclopropylpiperazin-1-yl)phenyl)urea;1-(4-(4,6-bis((1S,5S,6S)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(cyclopropylmethyl)piperazin-1-yl)phenyl)urea;1-(4-(4,6-bis((1S,5S,6S)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea;1-(4-(4,6-bis((1S,5S,6S)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-3-yl)urea;1-(4-(4,6-bis((1S,5S,6S)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazine-1-carbonyl)phenyl)urea;1-(4-(4,6-bis((1S,5S,6S)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-ethylpiperazine-1-carbonyl)phenyl)urea;1-(4-(4,6-bis((1S,5S,6S)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazine-1-carbonyl)phenyl)urea;1-(4-(4,6-bis((1S,5S,6S)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(dimethylamino)piperidine-1-carbonyl)phenyl)urea;1-(4-(4,6-bis((1S,5S,6S)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-cyclopropylpiperazine-1-carbonyl)phenyl)urea;1-(4-(4,6-bis((1S,5S,6S)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(cyclopropylmethyl)piperazine-1-carbonyl)phenyl)urea;1-(4-(4,6-bis((1S,5S,6R)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea;1-(4-(4,6-bis((1S,5S,6R)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazin-1-yl)phenyl)urea;1-(4-(4,6-bis((1S,5S,6R)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-ethylpiperazin-1-yl)phenyl)urea;1-(4-(4,6-bis((1S,5S,6R)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(dimethylamino)piperidin-1-yl)phenyl)urea;1-(4-(4,6-bis((1S,5S,6R)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(quinuclidin-4-yl)phenyl)urea;1-(4-(4,6-bis((1S,5S,6R)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-cyclopropylpiperazin-1-yl)phenyl)urea;1-(4-(4,6-bis((1S,5S,6R)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(cyclopropylmethyl)piperazin-1-yl)phenyl)urea;1-(4-(4,6-bis((1S,5S,6R)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea;1-(4-(4,6-bis((1S,5S,6R)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-3-yl)urea;1-(4-(4,6-bis((1S,5S,6R)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazine-1-carbonyl)phenyl)urea;1-(4-(4,6-bis((1S,5S,6R)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-ethylpiperazine-1-carbonyl)phenyl)urea;1-(4-(4,6-bis((1S,5S,6R)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazine-1-carbonyl)phenyl)urea;1-(4-(4,6-bis((1S,5S,6R)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(dimethylamino)piperidine-1-carbonyl)phenyl)urea;1-(4-(4,6-bis((1S,5S,6R)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-cyclopropylpiperazine-1-carbonyl)phenyl)urea;1-(4-(4,6-bis((1S,5S,6R)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(cyclopropylmethyl)piperazine-1-carbonyl)phenyl)urea;1-(4-(4-((1S,5S,6R)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((1S,5S,6S)-6-fluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea;1-(4-(4,6-bis(6,6-difluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea;1-(4-(4,6-bis(6,6-difluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazin-1-yl)phenyl)urea;1-(4-(4,6-bis(6,6-difluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-ethylpiperazin-1-yl)phenyl)urea;1-(4-(4,6-bis(6,6-difluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(dimethylamino)piperidin-1-yl)phenyl)urea;1-(4-(4,6-bis(6,6-difluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(quinuclidin-4-yl)phenyl)urea;1-(4-(4,6-bis(6,6-difluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-cyclopropylpiperazin-1-yl)phenyl)urea;1-(4-(4,6-bis(6,6-difluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(cyclopropylmethyl)piperazin-1-yl)phenyl)urea;1-(4-(4,6-bis(6,6-difluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea;1-(4-(4,6-bis(6,6-difluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-3-yl)urea;1-(4-(4,6-bis(6,6-difluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazine-1-carbonyl)phenyl)urea;1-(4-(4,6-bis(6,6-difluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-ethylpiperazine-1-carbonyl)phenyl)urea;1-(4-(4,6-bis(6,6-difluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazine-1-carbonyl)phenyl)urea;1-(4-(4,6-bis(6,6-difluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(dimethylamino)piperidine-1-carbonyl)phenyl)urea;1-(4-(4,6-bis(6,6-difluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-cyclopropylpiperazine-1-carbonyl)phenyl)urea;1-(4-(4,6-bis(6,6-difluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(cyclopropylmethyl)piperazine-1-carbonyl)phenyl)urea;1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(pyrimidin-5-yl)urea;1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(pyridazinyl-4-yl)urea;1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea;1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-3-yl)urea;1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(pyridazin-4-yl)urea;1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(pyrimidin-5-yl)urea;4-(3-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)ureido)benzamide;4-(3-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)ureido)-N-(2-(dimethylamino)ethyl)benzamide;4-(3-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)ureido)-N-(2-(methylamino)ethyl)benzamide;1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-((R)-3-(dimethylamino)pyrrolidine-1-carbonyl)phenyl)urea;1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(piperazine-1-carbonyl)phenyl)urea;1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazine-1-carbonyl)phenyl)urea;1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-ethylpiperazine-1-carbonyl)phenyl)urea;1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazine-1-carbonyl)phenyl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-3-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-3-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-3-yl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-3-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(pyridazin-4-yl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-3-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(pyrimidin-5-yl)urea;4-(3-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-3-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)ureido)benzamide;4-(3-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-3-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)ureido)-N-(2-(dimethylamino)ethyl)benzamide;4-(3-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-3-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)ureido)-N-(2-(methylamino)ethyl)benzamide;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-3-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-((R)-3-(dimethylamino)pyrrolidine-1-carbonyl)phenyl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-3-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(piperazine-1-carbonyl)phenyl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-3-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazine-1-carbonyl)phenyl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-3-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-ethylpiperazine-1-carbonyl)phenyl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-3-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazine-1-carbonyl)phenyl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-acetylphenyl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-(dimethylamino)acetyl)phenyl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-morpholinoacetyl)phenyl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-hydroxyacetyl)phenyl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(methoxymethyl)phenyl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-methoxyethyl)phenyl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(1-hydroxyethyl)phenyl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-hydroxypropan-2-yl)phenyl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-hydroxypropyl)phenyl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-hydroxy-2-methylpropyl)phenyl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(dimethylamino)piperidine-1-carbonyl)phenyl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-acetylphenyl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-(dimethylamino)acetyl)phenyl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-morpholinoacetyl)phenyl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-hydroxyacetyl)phenyl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(methoxymethyl)phenyl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-methoxyethyl)phenyl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(1-hydroxyethyl)phenyl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-hydroxypropan-2-yl)phenyl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-hydroxypropyl)phenyl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-hydroxy-2-methylpropyl)phenyl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(dimethylamino)piperidine-1-carbonyl)phenyl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-3-yl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(piperazin-1-yl)phenyl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-cyanophenyl)urea;4-(3-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)ureido)-N-methylbenzamide;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(6-(4-methylpiperazine-1-carbonyl)pyridin-3-yl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-((dimethylamino)methyl)phenyl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(piperazin-1-yl)phenyl)urea;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-cyanophenyl)urea;4-(3-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)ureido)benzamide;4-(3-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)ureido)-N,N-dimethylbenzamide;4-(3-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)ureido)-N-methylbenzamide;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(pyrrolidine-1-carbonyl)phenyl)urea;4-(3-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)ureido)-N-(2-(dimethylamino)ethyl)benzamide;4-(3-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)ureido)-N-(2-(methylamino)ethyl)benzamide;1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(6-(4-methylpiperazine-1-carbonyl)pyridin-3-yl)urea;1-(4-{[(3S)-3-(dimethylamino)pyrrolidin-1-yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;1-(4-{[(3R)-3-(dimethylamino)pyrrolidin-1-yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea;1-(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea;1-(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl}phenyl)-3-(4-{[4-(propan-2-yl)piperazin-1-yl]carbonyl}phenyl)urea;N-[2-(dimethylamino)ethyl]-N-methyl-4-{[(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl}phenyl)carbamoyl]amino}benzamide;4-{[(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl}phenyl)carbamoyl]amino}benzoicacid;1-(4-{[(3R)-3-(dimethylamino)pyrrolidin-1-yl]carbonyl}phenyl)-3-(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl}phenyl)urea;1-(4-{[(3S)-3-(dimethylamino)pyrrolidin-1-yl]carbonyl}phenyl)-3-(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl}phenyl)urea;1-(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl}phenyl)-3-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}urea;1-{4-[(4-ethylpiperazin-1-yl)carbonyl]phenyl}-3-(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl}phenyl)urea;1-{4-[4-(morpholin-4-yl)-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}-3-{4-[(3,3,4-trimethylpiperazin-1-yl)carbonyl]phenyl}urea;and1-(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl}phenyl)-3-[4-(piperazin-1-ylcarbonyl)phenyl]urea.13. The compound of claim 12, which is1-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea.14. A composition comprising a compound of claim 1 and apharmaceutically acceptable carrier.
 15. The composition of claim 14,wherein the pharmaceutically acceptable carrier suitable for oraladministration and the composition comprises an oral dosage form.
 16. Acomposition comprising a compound of claim 1; a second compound selectedfrom the group consisting of a topoisomerase I inhibitor, a MEK 1/2inhibitor, a HSP90 inhibitor, procarbazine, dacarbazine, gemcitabine,capecitabine, methotrexate, taxol, taxotere, mercaptopurine,thioguanine, hydroxyurea, cytarabine, cyclophosphamide, ifosfamide,nitrosoureas, cisplatin, carboplatin, mitomycin, dacarbazine,procarbizine, etoposide, teniposide, campathecins, bleomycin,doxorubicin, idarubicin, daunorubicin, dactinomycin, plicamycin,mitoxantrone, L-asparaginase, doxorubicin, epirubicin, 5-fluorouracil,docetaxel, paclitaxel, leucovorin, levamisole, irinotecan, estramustine,etoposide, nitrogen mustards, BCNU, carmustine, lomustine, vinblastine,vincristine, vinorelbine, cisplatin, carboplatin, oxaliplatin, imatinibmesylate, Avastin (bevacizumab), hexamethylmelamine, topotecan, tyrosinekinase inhibitors, tyrphostins, herbimycin A, genistein, erbstatin,hydroxyzine, glatiramer acetate, interferon beta-1a, interferon beta-1b,natalizumab and lavendustin A; and a pharmaceutically acceptablecarrier.
 17. The composition of claim 16, wherein the second compound isAvastin.
 18. A method of treating a PI3K-related disorder, comprisingadministering to a mammal in need thereof a compound of claim 1 in anamount effective to treat a PI3K-related disorder.
 19. The method ofclaim 18, wherein the PI3K-related disorder is selected from restenosis,atherosclerosis, bone disorders, arthritis, diabetic retinopathy,psoriasis, benign prostatic hypertrophy, atherosclerosis, inflammation,angiogenesis, immunological disorders, pancreatitis, kidney disease, andcancer.
 20. The method of claim 19, wherein the PI3K-related disorder iscancer.
 21. The method of claim 20, wherein the cancer is selected fromthe group consisting of leukemia, skin cancer, bladder cancer, breastcancer, uterus cancer, ovary cancer, prostate cancer, lung cancer, coloncancer, pancreas cancer, renal cancer, gastric cancer, and brain cancer.22. A method of treating an mTOR-related disorder, comprisingadministering to a mammal in need thereof a compound of claim 1 in anamount effective to treat an mTOR-related disorder.
 23. The method ofclaim 22, wherein the mTOR-related disorder is selected from restenosis,atherosclerosis, bone disorders, arthritis, diabetic retinopathy,psoriasis, benign prostatic hypertrophy, atherosclerosis, inflammation,angiogenesis, immunological disorders, pancreatitis, kidney disease, andcancer.
 24. The method of claim 23, wherein the mTOR-related disorder iscancer.
 25. The method of claim 24, wherein the cancer is selected fromthe group consisting of leukemia, skin cancer, bladder cancer, breastcancer, uterus cancer, ovary cancer, prostate cancer, lung cancer, coloncancer, pancreas cancer, renal cancer, gastric cancer, and brain cancer.26. A method of treating advanced renal cell carcinoma, comprisingadministering to a mammal in need thereof a compound of claim 1 in anamount effective to treat advanced renal cell carcinoma.
 27. A method oftreating acute lymphoblastic leukemia, comprising administering to amammal in need thereof a compound of claim 1 in an amount effective totreat acute lymphoblastic leukemia.
 28. A method of treating acutemalignant melanoma, comprising administering to a mammal in need thereofa compound of claim 1 in an amount effective to treat malignantmelanoma.
 29. A method of treating soft-tissue or bone sarcoma,comprising administering to a mammal in need thereof a compound of claim1 in an amount effective to treat soft-tissue or bone sarcoma.
 30. Amethod of treating a cancer selected from the group consisting ofleukemia, skin cancer, bladder cancer, breast cancer, uterus cancer,ovary cancer, prostate cancer, lung cancer, colon cancer, pancreascancer, renal cancer, gastric cancer, and brain cancer comprisingadministering to a mammal in need thereof the composition of claim 17 inan amount effective to treat the cancer.
 31. A method of inhibiting mTORin a subject, comprising administering to a subject in need thereof acompound of claim 1 in an amount effective to inhibit mTOR.
 32. A methodof inhibiting PI3K in a subject, comprising administering to a subjectin need thereof a compound of claim 1 in an amount effective to inhibitPI3K.
 33. A method of inhibiting mTOR, PI3K, and hSMG-1 together in asubject, comprising administering to a subject in need thereof acompound of claim 1 in an amount effective to inhibit mTOR, PI3K, andhSMG-1.
 34. A method of making a compound of claim 1 having the formula

said method comprising reacting 2,4,6-trichloro[1,3,5]triazine with

to form the intermediate dichlorotriazine compound


35. The method of claim 34 further comprising reacting the intermediatedichlorotriazine compound with

to form the intermediate compound


36. The method of claim 35 wherein the reacting moiety

is independently selected from